Process for preparing optically active secondary alcohols having nitrogenous or oxygenic functional groups

ABSTRACT

A process for preparing optically active secondary alcohols of the general formula (3), [wherein R 1  is linear lower alkyl, an aromatic ring group, or the like; A is CH 2 NR 2 R 3  or the like; n is an integer of 0 to 2; and * represents an asymmetric carbon atom] by asymmetrically hydrogenating a ketone compound of the general formula (1) having nitrogenous or oxygen functional group at any of the a-, β- and γ-positions, with selectivity among functional groups by the use of a ruthenium/optically active bidentate phosphine/diamine complex as the catalyst in the presence of hydrogen alone or together with a base. The optically active secondary alcohols obtained by the process are useful as drugs and intermediates for the preparation of drugs.

FIELD OF THE INVENTION

[0001] The present invention relates to a novel process of excellentpractical use for the preparation of optically active secondary alcoholshaving a nitrogenous or oxygenic functional group which comprisesasymmetrically hydrogenating a ketone compound having a nitrogenous oroxygenic functional group at any of the α-, β- and γ-positions with aruthenium/optically active bidentate phosphine/diamine complex as acatalyst in the presence of hydrogen or in the presence of hydrogen anda base with good selectivity for the functional groups, goodenantioselectivity and high efficient.

BACKGROUND OF THE INVENTION

[0002] Transition metal complexes have been reported as being a usefulcatalyst for a variety of homogeneous catalytic reactions orheterogeneous catalytic reactions. However, universally applicable,highly practical, highly efficient and highly selective catalysts forhydrogenation reaction of ketone compounds having a nitrogenous oroxygenic functional group have not been developed. A process forpreparing alcohol compounds comprising hydrogenating carbonyl compoundswith a homogeneous catalyst to yield the corresponding alcohol compoundshas been well known. Examples of the process include, for example, theprocess using a ruthenium complex, described in (Literature 1) Eds. G.Wilkinson, F. G. A. Stone and E. W. Abel, Comprehensive OrganometallicChemistry, Vol. 4, p. 931 (1982); the processes using an rhodiumcomplex, described in (Literature 2) Inorg. Nucl. Chem. Letters, Vol.12, p. 865 (1976), J. Organomet. Chem., Vol. 129, p. 239 (1977), Chem.Letters, p. 261 (1982), and Tetrahedron Letters, Vol. 35, p. 4963(1994); and the process using a iridium complex, described in(Literature 3) J. Am. Chem. Soc., Vol. 115, p. 3318 (1993).

[0003] When viewed from obtaining optically active alcohol compounds,some processes which include a process using an enzyme such as baker'syeast, and a process comprising asymmetrically hydrogenating a carbonylcompound with a metal complex catalyst have been known. With respect tothe latter process, many examples of asymmetric catalytic reaction havebeen reported. The examples include, for example, the process forasymmetrically hydrogenating a functional group containing carbonylcompound with an optically active ruthenium catalyst, described indetail in (Literature 4) Asymmetric Catalysis in Organic Synthesis, pp.56-82 (1994) Ed. R. Noyori; the process comprising ahydrogen-transferring reductive reaction using a ruthenium-, rhodium- oriridium-based asymmetric complex catalyst, described in (Literature 5)Chem. Rev., Vol. 92, pp. 1051-1069 (1992); the processes comprising anasymmetric hydrogenation reaction using nickel catalyst modified withtartaric acid, described in (Literature 6) Oil Chemistry, pp. 822-831(1980).and Ed. Y. Izumi, and Advances in Catalysis, Vol. 32, p. 215(1983); the process comprising an asymmetric hydrosilylation reaction,described in (Literature 7) Asymmetric Synthesis, Vol. 5, Chap. 4 (1985)Ed. J. D. Morrison, and J. Organomet. Chem., Vol. 346, pp. 413-424(1988); the processes comprising reducing borane in the presence of anasymmetric ligand, described in (Literature 8) J. Chem. Soc. PerkinTrans. 1, pp. 2039-2044 (1985) and J. Am. Chem. Soc., Vol. 109, pp.5551-5553 (1987); the process comprising an asymmetric hydrogenationreaction using a ruthenium/optically active phosphine complex, describedin (Literature 9) JP-A-4-187685; the process comprising an asymmetrichydrogenation reaction in the presence of phosphine and diamineasymmetric ligand, described in (Literature 10) J. Am. Chem. Soc., Vol.117, pp. 2675-2676 (1995); the process comprising an asymmetrichydrogenation reaction using a rhodium complex, described in (Literature11) Tetrahedron Letters, Vol. 40(24), pp. 4551-4554 (1999); and, theprocess using a cationic ruthenium/BINAP complex, such as[RuI((S)-BINAP) (p-cymene)]⁺I⁻, described in (Literature 12) J. Org.Chem., Vol. 59, pp. 3064-3076 (1994).

[0004] However, these conventional processes have a problem that theyare not necessarily practically useful due to the facts that they use anoble metal complex catalyst based on a relatively costly metal such asrhodium, iridium, palladium or platinum; have a low hydrogenatingactivity; and require a relatively high reaction temperature or hydrogenpressure. The process using an enzyme, which can afford an alcoholcompound having a relatively high optical purity, has disadvantages thatthe nature of reaction substrates to be used is limited and that theabsolute configuration of alcohol compounds obtained is limited tospecific ones.

[0005] Further, the conventional process using an asymmetrichydrogenation catalyst based on a transition metal, which can produceoptically active alcohol compounds with a high selectivity with respectto the reaction substrates such as keto acid derivatives, also has thefollowing drawbacks relating to the catalytic activity. For example, thenature of reaction substrates to be used is limited; a relatively highhydrogen pressure is required when the process is carried out at normaltemperature; and a heating treatment is required when the hydrogenpressure is not high. Further, although the process described in theabovementioned Literature 10, which is excellent in the selectivity andactivity, it has the following drawbacks. That is, the process needs acomplicated handling comprising mixing tree components which areruthenium phosphine complex having poor long-term storage stability,diamine compound and base, on occasion. Further, when an aminoketonecompound is used as the substrate, the decomposition thereof goes aheadof the reaction of interest. Further, the process described inLiterature 12, which can reduce 1-dimethyl aminoacetone with a highenantioselectivity, is not necessarily suitable to industrial use fromthe viewpoint of the catalytic activity due to the following drawbacks.That is, for example, the kinds of substrate ketone compound to be usedare limited; the process requires a high pressure of about 100 atm; anda relatively long reaction time is needed.

[0006] Consequently, there has been a need for a catalyst havinguniversal applicability, high activity, high functionalgroup-selectivity and high enantioselectivity which can be used toasymmetrically hydrogenate ketone compounds having a nitrogenous oroxygenic functional group at any of the α-, β- and γ-positions todirectly produce the corresponding optically active secondary alcoholshaving a nitrogenous or oxygenic functional group at any of the α-, β-and γ-positions which are widely used as medicaments or an intermediatefor producing especially medicaments, or to produce the correspondingoptically active secondary alcohols via sequential steps of suitablyremoving the protecting groups and transforming the functional groups.There has been also a need for a practical process using the abovecatalyst. An object of the present invention is to provide such acatalyst and a process for producing optically active secondary alcoholshaving a nitrogenous or oxygenic functional group.

DISCLOSURE OF THE INVENTION

[0007] In order to solve the above problems, the present inventorsconducted a variety of studies. As a result, the present inventors havefound a characteristic ruthenium/optically active bidentatephosphine/diamine complex which can reductively hydrogenate ketonecompounds having a nitrogenous or oxygenic functional group at any ofthe α-, β- and γ-positions with high selectivity under a mild conditionto afford the corresponding optically active secondary alcohols withgood enantioselectivity and good yield, and thereby completed thepresent invention.

[0008] That is, the present invention relates to a process for thepreparation of an optically active secondary alcohol represented by thegeneral formula (3) having a nitrogenous or oxygenic functional group atany of the α-, β- and γ-positions:

[0009] wherein

[0010] n is an integer of from 0 to 2;

[0011] R¹ represents:

[0012] (a) a straight-chain lower alkyl group,

[0013] (b) an optionally substituted monocyclic aromatic hydrocarbonring group,

[0014] (c) an optionally substituted fused bicyclic aromatic hydrocarbonring group,

[0015] (d) an optionally substituted fused tricyclic aromatichydrocarbon ring group,

[0016] (e) an optionally substituted monocyclic heteroaromatic ringgroup,

[0017] (f) an optionally substituted fused bicyclic heteroaromatic ringgroup, or

[0018] (g) an optionally substituted fused tricyclic heteroaromatic ringgroup;

[0019] A represents:

[0020] (a) CH₂NR²R³,

[0021] (b) CH₂OR⁴, or

[0022] (c) CH(OR¹⁵)₂;

[0023] R² represents:

[0024] (a) an acyl or alkyloxycarbonyl group,

[0025] (b) an optionally substituted straight-chain alkyl group,

[0026] (c) an optionally substituted branched-chain alkyl group,

[0027] (d) an optionally substituted cyclic alkyl group,

[0028] (e) an optionally substituted alkenyl group,

[0029] (f) an optionally substituted aralkyl group,

[0030] (g) an optionally substituted aryl group,

[0031] (h) a heteroatom-containing saturated carbon chain group,

[0032] (i) a heteroatom-containing unsaturated carbon chain group,

[0033] (j) an optionally substituted heteromonocyclic group,

[0034] (k) an optionally substituted heteropolycyclic group, or

[0035] (l) a composite group consisting of members suitably selectedfrom any of (b) to (k);

[0036] when R² is (a) an acyl or alkyloxycarbonyl group among the abovegroups, R³ represents:

[0037] (a) hydrogen,

[0038] (b) an optionally substituted straight-chain alkyl group,

[0039] (c) an optionally substituted branched-chain alkyl group,

[0040] (d) an optionally substituted cyclic alkyl group,

[0041] (e) an optionally substituted alkenyl group,

[0042] (f) an optionally substituted aralkyl group,

[0043] (g) an optionally substituted aryl group,

[0044] (h) a heteroatom-containing saturated carbon chain group,

[0045] (i) a heteroatom-containing unsaturated carbon chain group,

[0046] (j) an optionally substituted heteromonocyclic group,

[0047] (k) an optionally substituted heteropolycyclic group, or

[0048] (l) a composite group consisting of members suitably selectedfrom any of (b) to (k);

[0049] alternatively, when R² is any group other than (a) an acyl oralkyloxycarbonyl group among the above groups, R³ represents:

[0050] (a) an optionally substituted straight-chain alkyl group,

[0051] (b) an optionally substituted branched-chain alkyl group,

[0052] (c) an optionally substituted cyclic alkyl group,

[0053] (d) an optionally substituted alkenyl group,

[0054] (e) an optionally substituted aralkyl group,

[0055] (f) an optionally substituted aryl group,

[0056] (g) a heteroatom-containing saturated carbon chain group,

[0057] (h) a heteroatom-containing unsaturated carbon chain group,

[0058] (i) an optionally substituted heteromonocyclic group,

[0059] (j) an optionally substituted heteropolycyclic group, or

[0060] (k) a composite group consisting of members suitably selectedfrom any of (a) to (j); and R² and R³ may be linked to each other toform a heterocyclic group;

[0061] R⁴ represents:

[0062] (a) an optionally substituted straight-chain alkyl group,

[0063] (b) an optionally substituted branched-chain alkyl group,

[0064] (c) an optionally substituted cyclic alkyl group,

[0065] (d) an optionally substituted benzyl group,

[0066] (e) an optionally substituted aralkyl group,

[0067] (f) an optionally substituted aryl group,

[0068] (g) a heteroatom-containing saturated carbon chain group,

[0069] (h) a heteroatom-containing unsaturated carbon chain group,

[0070] (i) an optionally substituted heteromonocyclic group

[0071] (j) an optionally substituted heteropolycyclic group,

[0072] (k) a composite group consisting of members suitably selectedfrom any of (a) to (j), or

[0073] (l) an organosilicon group represented by SiR⁵R⁶R⁷;

[0074] R⁵, R⁶ and R⁷ each independently represent:

[0075] (a) a straight-chain or branched-chain lower alkyl group, or

[0076] (b) a phenyl group;

[0077] R¹⁵ represents:

[0078] (a) a straight-chain lower alkyl group,

[0079] (b) a branched-chain lower alkyl group,

[0080] (c) a cyclic lower alkyl group,

[0081] (d) an optionally substituted phenyl group,

[0082] (e) an optionally substituted benzyl group, or

[0083] (f) alternatively, two R¹⁵ are bonded to each other to form acyclic ketal group; and

[0084] * represents an asymmetric carbon atom,

[0085] which comprises asymmetrically hydrogenating a ketone compoundrepresented by the general formula (1) having a nitrogenous or oxygenicfunctional group at any of the α-, β- and γ-positions:

[0086] wherein R¹, A and n are as defined above, or a mineral or organicacid salt thereof, with a catalyst in the presence of hydrogen or in thepresence of hydrogen and a base, the catalyst being aruthenium/optically active bidentate phosphine/diamine complexrepresented by the general formula (2):

[0087] wherein

[0088] m is an integer of from 0 to 2;

[0089] X and Y may be covalently or ionically bonded to the rutheniummetal, and they independently represent:

[0090] (a) hydrogen,

[0091] (b) halogen,

[0092] (c) an alkoxy group,

[0093] (d) a carboxyl group, or

[0094] (e) other anion radical;

[0095] Ar¹ and Ar² independently represent a phenyl group substitutedwith from zero to five substituents selected from straight-chain orbranched-chain lower alkyl group, halogen or lower alkoxy group;

[0096] R⁸ represents:

[0097] (a) hydrogen,

[0098] (b) a lower alkyl group,

[0099] (c) a lower alkoxy group, or

[0100] (d) N(R¹⁴)₂ wherein R¹⁴ represents a lower alkyl group;

[0101] R⁹ represents:

[0102] (a) hydrogen,

[0103] (b) a lower alkyl group, or

[0104] (c) a lower alkoxy group;

[0105] R¹⁰ represents:

[0106] (a) a lower alkyl group, or

[0107] (b) a lower alkoxy group;

[0108] the dashed line linking one R¹⁰ to the other R¹⁰ means that oneR¹⁰ may be bonded to the other R¹⁰ via an oxygen atom;

[0109] one dashed line linking R⁹ to R¹⁰, and the other dashed linelinking R⁹ to R¹⁰ independently mean that each pair of R⁹ and R¹⁰ takentogether with the benzene ring to which they are attached may form aring selected from the following rings:

[0110] (a) an optionally substituted tetralin ring,

[0111] (b) an optionally substituted naphthalene ring, and

[0112] (c) an optionally substituted 1,3-benzodioxole ring;

[0113] R¹¹ represents:

[0114] (a) hydrogen,

[0115] (b) a straight-chain lower alkyl group,

[0116] (c) a branched-chain lower alkyl group,

[0117] (d) a cyclic lower alkyl group,

[0118] (e) a phenyl group substituted with from zero to fivesubstituents selected from lower alkyl groups or lower alkoxy groups,

[0119] (f) a 1-naphthyl group substituted with from zero to sevensubstituents selected from lower alkyl groups or lower alkoxy groups, or

[0120] (g) a 2-naphthyl group substituted with from zero to sevensubstituents selected from lower alkyl groups or lower alkoxy groups;

[0121] provided that (I) when R¹¹ is hydrogen, then R¹² and R¹³ areindependently represent:

[0122] (a) hydrogen,

[0123] (b) a straight-chain lower alkyl group,

[0124] (c) a branched-chain lower alkyl group,

[0125] (d) a cyclic lower alkyl group,

[0126] (e) a phenyl group substituted with from zero to fivesubstituents selected from lower alkyl groups or lower alkoxy groups,

[0127] (f) a 1-naphthyl group substituted with from zero to sevensubstituents selected from lower alkyl groups or lower alkoxy groups,

[0128] (g) a 2-naphthyl group substituted with from zero to sevensubstituents selected from lower alkyl groups or lower alkoxy groups, or

[0129] (h) alternatively, R¹² and R¹³ may be bonded to each other toform a ring selected from:

[0130] (h-i) a cycloalkyl ring, or

[0131] (h-2) a heteroatom-containing heterocyclic ring; or

[0132] (II) when R¹¹ is other than hydrogen, then R¹² represents:

[0133] (a) a straight-chain lower alkyl group,

[0134] (b) a branched-chain lower alkyl group,

[0135] (c) a cyclic lower alkyl group,

[0136] (d) a phenyl group substituted with from zero to fivesubstituents selected from lower alkyl groups or lower alkoxy groups,

[0137] (e) a 1-naphthyl group substituted with from zero to sevensubstituents selected from lower alkyl groups or lower alkoxy groups, or

[0138] (f) a 2-naphthyl group substituted with from zero to sevensubstituents selected from lower alkyl groups or lower alkoxy groups;and

[0139] R¹³ represents:

[0140] (a) hydrogen,

[0141] (b) a lower alkyl group, or

[0142] (c) a benzyl group.

[0143] Further, the present invention is also a process for thepreparation of an optically active secondary alcohol, wherein R¹ and Ain the general formula (1) set forth above comprise no acidicsubstituents.

[0144] Further, the present invention is also a process for thepreparation of an optically active secondary alcohol, wherein Ar¹ andAr² in the general formula (2) set forth above independently represent aphenyl group having from two to five substituents selected from thegroup consisting of straight-chain or branched-chain lower alkyl groups,halogens, or lower alkoxy groups provided that at least two of the saidsubstituents are straight-chain or branched-chain lower alkyl groups.

[0145] Further, the present invention is also a process for thepreparation of an optically active secondary alcohol, wherein in thegeneral formula (1) set forth above, n is 0; A is CH₂NR²R³; R¹ is aphenyl group having at 3-position a nitro group, an amino group, orN(CH₂C₆H₅)SO₂R¹⁶ wherein R¹ is a methyl group or a benzyl group, and at4-position hydrogen, halogen, or a benzyloxy group; R² is an acyl group,an alkyloxycarbonyl group, or a benzyl group; and R³ is an ethyl groupwhich is bonded at its end to the fused tricyclic ring group via anoxygen atom.

[0146] Further, the present invention provides a practical process forthe preparation of optically active secondary alcohols containing anamino group, optically active diols and optically activehydroxyaldehydes which are useful in a variety of applications, forexample, as an intermediate for producing medicaments and pesticides oras medicaments and pesticides per se, wherein the process comprisessequentially or simultaneously removing the nitrogen- andoxygen-protecting groups of the optically active secondary alcoholsobtained by the preparing process set forth above.

[0147] Further, the present invention also provides a process for thepreparation of an optically active secondary alcohol containing an aminogroup, wherein the process comprises converting a terminal primaryhydroxyl group of an optically active diol into a leaving group by aconventional method; when the diol is an optically active 1,2-diol,optionally converting it into an optically active epoxy compound; andreacting the reaction product with a primary or secondary aminecompound.

[0148] Further, the present invention also provides a short process forthe preparation of an optically active secondary alcohol containing anamino group, wherein the process comprises converting an opticallyactive secondary alcohol having a terminal aldehyde group protected asketal into the corresponding optically active imino alcohol bydeprotecting the aldehyde group followed by a reaction with a primaryamine compound; and subjecting the thus obtained imino alcohol to aconventional imine-reducing reaction. Examples of such an opticallyactive secondary alcohol containing an amino group which is particularlyimportant as an medicament, may be mentioned as follows. For example,examples of the alcohol compound having an amino group at the α-positioninclude adrenaline derivatives having an activity as a sympatheticreceptor agonist or antagonist, such as an antiasthmatic agent acting onthe bronchial smooth muscle and a vasopressor acting on the heart.Compounds disclosed in WO 97/25311 and WO 99/01431 are described thereinas being very useful for treating and preventing diabetes, obesity,hyperlipidemia and the like. Examples of the alcohol compound having anamino group at the β-position include compounds acting on the centralnervous system, such as trihexyphenidyl hydrochloride which is anantiparkinson agent. Examples of the alcohol compound having an aminogroup at the γ-position include nonsedating histamine H₁-receptorantagonists (allergic disease-treating agents) such as Terfenadine,antipsychotic agents such as BMS 181100 (described in the literature: J.Med. Chem., Vol. 35, 4516-4525 (1992)), and drugs acting on the centralnervous system.

[0149] The disclosures in the text of specification and/or drawings ofJapanese Patent Application No. 2000-30127, from which the presentapplication claims the priority right, is incorporated herein.

PREFERRED EMBODIMENTS OF THE INVENTION

[0150] The present invention has the technical features set forth above.Preferred embodiments of the present invention will be described belowin more detail. As a reaction substrate, ketone compounds having anitrogenous or oxygenic functional group at any of the α-, β- andγ-positions are represented by the general formula (1) wherein nrepresents an integer of from 0 to 2, with 0 being preferred.

[0151] R¹ represents:

[0152] (a) a straight-chain lower alkyl group,

[0153] (b) an optionally substituted monocyclic aromatic hydrocarbonring group,

[0154] (c) an optionally substituted fused bicyclic aromatic hydrocarbonring group,

[0155] (d) an optionally substituted fused tricyclic aromatichydrocarbon ring group,

[0156] (e) an optionally substituted monocyclic heteroaromatic ringgroup,

[0157] (f) an optionally substituted fused bicyclic heteroaromatic ringgroup, or

[0158] (g) an optionally substituted fused tricyclic heteroaromatic ringgroup.

[0159] With respect to the groups represented by R¹, (a) astraight-chain lower alkyl group means a straight-chain alkyl grouphaving from one to six carbon atoms. “Optionally substituted group”referred to in (b) to (g) means a group optionally substituted with fromone to nine substituents which may be the same or different from eachother.

[0160] The substituents include alkyl group, alkoxy group, halogen,alkenyl group, nitro group, amino group,-acylated amino group,alkylsulfonylated amino group, and cyano group. The substituentspreferably comprise no acidic functional groups such as phenolichydroxyl group and carboxylic acid group.

[0161] Examples of (a) a straight-chain lower alkyl group include methylgroup, ethyl group, n-propyl group, n-butyl group, n-pentyl group, andn-hexyl group, with methyl group being preferred.

[0162] Examples of (b) an optionally substituted monocyclic aromatichydrocarbon ring group include 3-aminophenyl group, 3-nitrophenyl group,3-[(benzyl)(methylsulfonyl)amino]phenyl group,3-[(benzyl)(benzylsulfonyl)amino]phenyl group, 4-methoxyphenyl group,4-nitrophenyl group, 4-chlorophenyl group, 4-bromophenyl group,4-benzyloxyphenyl group, 3,4-dichlorophenyl group, 3,4-dibromophenylgroup, 4-chloro-3-aminophenyl group,4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-chloro-3-[(benzyl)(benzylsulfonyl)amino]phenyl group,4-chloro-3-nitrophenyl group, 4-bromo-3-aminophenyl group,4-bromo-3-[(benzyl)(methylsulfonyl)-amino]phenyl group,4-bromo-3-[(benzyl)(benzylsulfonyl)amino]phenyl group,4-bromo-3-nitrophenyl group, 4-benzyloxy-3-nitrophenyl group,4-benzyloxy-3-aminophenyl group,4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl group,4-benzyloxy-3-[(hydroxy)methyl]phenyl group, and xylyl group.

[0163] More preferred examples of (b) include 3-aminophenyl group,3-nitrophenyl group, 3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-methoxyphenyl group, 4-benzyloxyphenyl group, 4-chloro-3-aminophenylgroup, 4-chloro-3-[(benzyl) (methylsulfonyl)amino]phenyl group,4-chloro-3-nitrophenyl group, 4-bromo-3-aminophenyl group,4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-bromo-3-nitrophenyl group, 4-benzyloxy-3-nitrophenyl group,4-benzyloxy-3-aminophenyl group,4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl group, and4-benzyloxy-3-[(hydroxy)methyl]phenyl group.

[0164] Examples of (c) an optionally substituted fused bicyclic aromatichydrocarbon ring group include 1-naphthyl group, 2-naphthyl group,2-indenyl group, 3-indenyl group, 4-indenyl group, 5-indenyl group,6-indenyl group, 7-indenyl group and the like, with 1-naphthyl group and2-naphthyl group being more preferred.

[0165] Examples of (d) an optionally substituted fused tricyclicaromatic hydrocarbon ring group include anthracenyl group, phenanthrenylgroup, fluorenyl group and the like.

[0166] Examples of (e) an optionally substituted monocyclicheteroaromatic ring group include 2-thienyl group, 3-thienyl group,2-furyl group, 3-furyl group, 3-pyrrolyl group, 3-pyrazolyl group,4-pyrazolyl group, 4-imidazolyl group, oxazolyl group, isoxazolyl group,thiazolyl group, 3-pyranyl group, 4-pyranyl group, 5-pyranyl group,6-pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl group,pyrazinyl group, oxazinyl group, triazinyl group and the like, with3-furyl group and pyridyl group being more preferred.

[0167] Examples of (f) an optionally substituted fused bicyclicheteroaromatic ring group include xanthenyl group, 3-indolyl group,4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group,4-isoindolyl group, 5-isoindolyl group, 6-isoindolyl group, 7-isoindolylgroup, 4-benzimidazolyl group, 5-benzimidazolyl group, 6-benzimidazolylgroup, 7-benzimidazolyl group, benzofuranyl group, 4-dihydrobenzofuranylgroup, 5-dihydrobenzofuranyl group, 6-dihydrobenzofuranyl group,7-dihydrobenzofuranyl group, thionaphthenyl group, benzoxazolyl group,quinolyl group, isoquinolyl group, quinolizinyl group, quinoxalinylgroup, phthalazinyl group, naphthyridinyl group and the like.

[0168] Preferred examples include 3-indolyl group, 4-indolyl group,6-indolyl group, 4-benzimidazolyl group, 5-benzimidazolyl group,6-benzimidazolyl group, 7-benzimidazolyl group, 4-benzofuranyl group,5-benzofuranyl group, 6-benzofuranyl group, 4-dihydrobenzofuranyl group,5-dihydrobenzofuranyl group, 6-dihydrobenzofuranyl group, 4-benzoxazolylgroup, 5-benzoxazolyl group, 6-benzoxazolyl group, 7-benzoxazolyl group,and quinoxalinyl group.

[0169] More preferred examples include 4-indolyl group, 6-indolyl group,4-benzimidazolyl group, 5-benzimidazolyl group, 6-benzimidazolyl group,4-benzoxazolyl group, and 6-benzoxazolyl group.

[0170] Examples of (g) an optionally substituted fused tricyclicheteroaromatic ring group include acridinyl group, thianthracenyl group,phenoxazinyl group, phenothiazinyl group, carbazolyl group,dibenzofuranyl group, and dibenzothiophenyl group, with acridinyl groupand phenoxazinyl group being preferred.

[0171] Among the abovementioned groups, R¹ is preferably:

[0172] (b) an optionally substituted monocyclic aromatic hydrocarbonring group,

[0173] (c) an optionally substituted fused bicyclic aromatic hydrocarbonring group,

[0174] (e) an optionally substituted monocyclic heteroaromatic ringgroup, or

[0175] (f) an optionally substituted fused bicyclic heteroaromatic ringgroup;

[0176] more preferably:

[0177] (b) an optionally substituted monocyclic aromatic hydrocarbonring group,

[0178] (c) an optionally substituted fused bicyclic aromatic hydrocarbonfused ring group, or

[0179] (f) an optionally substituted fused bicyclic heteroaromatic ringgroup; and

[0180] still more preferably:

[0181] (b) an optionally substituted monocyclic aromatic hydrocarbonring group, or

[0182] (f) an optionally substituted fused bicyclic heteroaromatic fusedring group.

[0183] A represents (a) CH₂NR²R³, (b) CH₂OR⁴, or (c) CH(OR¹⁵)₂, with (a)CH₂NR²R³ being preferred.

[0184] R² represents:

[0185] (a) an acyl or alkyloxycarbonyl group,

[0186] (b) an optionally substituted straight-chain alkyl group,

[0187] (c) an optionally substituted branched-chain alkyl group,

[0188] (d) an optionally substituted cyclic alkyl group,

[0189] (e) an optionally substituted alkenyl group,

[0190] (f) an optionally substituted aralkyl group,

[0191] (g) an optionally substituted aryl group,

[0192] (h) a heteroatom-containing saturated carbon chain group,

[0193] (i) a heteroatom-containing unsaturated carbon chain group,

[0194] (j) an optionally substituted heteromonocyclic group,

[0195] (k) an optionally substituted heteropolycyclic group, or

[0196] (l) a composite group consisting of members suitably selectedfrom any of (b) to (k).

[0197] With respect to the groups represented by R², “optionallysubstituted group” referred to in (b) to (g), (j) and (k) means a groupoptionally substituted with from one to twenty substituents which may bethe same or different from each other, preferably a group optionallysubstituted with from one to nine substituents which may be the same ordifferent from each other, and more preferably a group optionallysubstituted with from one to five substituents which may be the same ordifferent from each other.

[0198] The substituents may include alkyl group, alkoxy group, halogen,alkenyl group, nitro group, amino group, acylated amino group,alkylsulfonylated amino group, cyano group, hydroxyl group protectedwith silyl group, and aryloxy group. The substituents preferablycomprise no acidic functional groups such as phenolic hydroxyl group andcarboxylic acid group.

[0199] Members of (a) an acyl group and alkyloxycarbonyl group are notlimited as long as they are those commonly used, and preferred examplesinclude acyl groups derived from alkylcarboxylic acid, such as formylgroup, acetyl group, propionyl group, butyryl group, pentanoyl group,hexanoyl group, trifluoroacetyl group, and pivaloyl group; acyl groupsderived from aromatic carboxylic acid, such as benzoyl group,4-methoxybenzoyl group, 2,4,6-trimethylbenzoyl group, naphthoyl groupand the like; and carbamate type protecting groups, such astert-butoxycarbonyl group, benzyloxycarbonyl group,p-methoxybenzylcarbonyl group, 2,2,2-trichloroethoxycarbonyl group andthe like. More preferred examples include acetyl group, benzoyl group,and tert-butoxycarbonyl group.

[0200] Examples of (b) an optionally substituted straight-chain alkylgroup include methyl group, ethyl group, propyl group, butyl group,pentyl group, hexyl group and the like, with methyl group beingpreferred.

[0201] Examples of (c) an optionally substituted branched-chain alkylgroup include isopropyl group, isobutyl group, sec-butyl group,tert-butyl group, cyclopropylmethyl group, cyclopropylethyl group,cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group,cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethyl groupand the like, with isopropyl group, tert-butyl group, cyclopentylmethylgroup, and cyclohexylmethyl group being preferred.

[0202] Examples of (d) an optionally substituted cyclic alkyl groupinclude cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, cycloheptyl group and the like, with cyclopropyl groupbeing preferred.

[0203] Examples of (e) an optionally substituted alkenyl group includeallyl group and vinyl group, with allyl group being preferred.

[0204] Examples of (f) an optionally substituted aralkyl group includebenzyl group, p-methoxybenzyl group, p-nitrobenzyl group and the like,with benzyl group and p-methoxybenzyl group being preferred.

[0205] Examples of (g) an optionally substituted aryl group includephenyl group, substituted phenyl group, naphthyl group, substitutednaphthyl group, anthryl group, substituted anthryl group, phenanthrylgroup, substituted phenanthryl group, indenyl group, substituted indenylgroup, fluorenyl group, substituted fluorenyl group and the like, withphenyl group, substituted phenyl group, naphthyl group, and substitutednaphthyl group being preferred.

[0206] Examples of (h) an heteroatom-containing saturated carbon chaingroup include:

[0207] (h-1) methyl group, ethyl group, propyl group, butyl group,pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butylgroup, tert-butyl group, cyclopropylmethyl group, cyclopropylethylgroup, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethylgroup, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethylgroup, and the like which are substituted directly with an optionallysubstituted heteroaromatic ring group;

[0208] (h-2) methyl group, ethyl group, propyl group, butyl group,pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butylgroup, tert-butyl group, cyclopropylmethyl group, cyclopropylethylgroup, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethylgroup, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethylgroup, and the like which are substituted with a heteroatom existing asa substituent on an optionally substituted heteroaromatic ring group;

[0209] (h-3) methyl group, ethyl group, propyl group, butyl group,pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butylgroup, tert-butyl group, cyclopropylmethyl group, cyclopropylethylgroup, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethylgroup, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethylgroup, and the like which are substituted directly with an optionallysubstituted saturated heterocyclic ring group; and

[0210] (h-4) methyl group, ethyl group, propyl group, butyl group,pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butylgroup, tert-butyl group, cyclopropylmethyl group, cyclopropylethylgroup, cyclobutylmethyl group, cyclobutylethyl group, cyclopentyl-methylgroup, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethylgroup, and the like which are substituted with a heteroatom existing asa substituent on an optionally substituted saturated heterocyclic ringgroup.

[0211] A heteroatom-containing saturated carbon chain group as (h) ispreferably selected from (h-1) and (h-2), and more preferably from(h-2).

[0212] In (h-2), the heteroatom-containing saturated carbon chain groupis preferably methyl, ethyl, propyl, butyl, pentyl or hexyl groupsubstituted with a heteroatom existing as a substituent on an optionallysubstituted heteroaromatic ring group, and more preferably methyl orethyl group substituted with a heteroatom existing as a substituent onan optionally substituted hetero-aromatic ring group. In addition,“heteroatom existing as a substituent” is preferably oxygen atom ornitrogen atom, and more preferably oxygen atom.

[0213] With respect to (h-1) and (h-2), examples of “optionallysubstituted heteroaromatic ring group” include thienyl group, furylgroup, pyrrolyl group, pyrazolyl group, imidazolyl group, oxazolylgroup, isoxazolyl group, thiazolyl group, pyridyl group, pyridazinylgroup, pyrimidinyl group, pyrazinyl group, oxazinyl group, triazinylgroup, indolyl group, isoindolyl group, benzimidazolyl group,benzofuranyl group, dihydrobenzofuranyl group, thionaphthenyl group,dihydrothionaphthenyl group, benzoxazolyl group, quinolyl group,isoquinolyl group, quinolizinyl group, quinoxalinyl group, phthalazinylgroup, naphthyridinyl group, acridinyl group, phenoxazinyl group,phenothiazinyl group, purinyl group, xanthinyl group, pteridinyl group,carbazolyl group, dibenzofuranyl group, dibenzothiophenyl group,tetrahydrocarbazolyl group, tetrahydrodibenzofuranyl group,tetrahydrodibenzothiophenyl group and the like. Preferred examplesinclude indolyl group, benzimidazolyl group, benzofuranyl group,benzoxazolyl group, quinolyl group, isoquinolyl group, phenoxazinylgroup, phenothiazinyl group, carbazolyl group, dibenzofuranyl group,dibenzothiophenyl group, tetrahydro-carbazolyl group,tetrahydrodibenzofuranyl group, and tetrahydrodibenzothiophenyl group.More preferred examples include carbazolyl group, dibenzofuranyl group,dibenzothiophenyl group, tetrahydrocarbazolyl group,tetrahydrodibenzofuranyl group, and tetrahydrodibenzothiophenyl group.

[0214] With respect to (h-3) and (h-4), examples of “optionallysubstituted saturated heterocyclic ring group” include tetrahydrofuranylgroup, tetrahydrothienyl group, pyrrolidinyl group, pyrazolonyl group,isoimidazolyl group, imidazolinyl group, imidazolidinyl group,oxazolinyl group, oxazolidinyl group, pyranyl group, thiazinyl group,orthooxazinyl group, oxazinyl group, piperidyl group, piperazinyl group,homopiperazinyl group, dioxanyl group, morpholinyl group, thioxanylgroup, thiomorpholinyl group and the like, with pyrrolidinyl group,piperazinyl group, homopiperazinyl group, dioxanyl group, andmorpholinyl group being preferred.

[0215] In addition, with respect to (h-2) and (h-4), “heteroatomexisting as a substituent” may be oxygen atom, nitrogen atom, or sulfuratom, with oxygen atom and nitrogen atom being more preferred.

[0216] Examples of (i) a heteroatom-containing unsaturated carbon chaingroup include:

[0217] (i-1) ethylene group, propylene group, butenyl group, pentenylgroup, hexenyl group, and the like which are substituted directly withan optionally substituted heteroaromatic ring group;

[0218] (i-2) ethylene group, propylene group, butenyl group, pentenylgroup, hexenyl group, and the like which are substituted with aheteroatom existing as a substituent on an optionally substitutedhetero-aromatic ring group;

[0219] (i-3) ethylene group, propylene group, butenyl group, pentenylgroup, hexenyl group, and the like which are substituted directly withan optionally substituted saturated heterocyclic ring group; and

[0220] (i-4) ethylene group, propylene group, butenyl group, pentenylgroup, hexenyl group, and the like which are substituted with aheteroatom existing as a substituent on an-optionally substitutedsaturated heterocyclic ring group.

[0221] A heteroatom-containing unsaturated carbon chain group as (i) ispreferably selected from (i-1) and (i-3), and more preferably from(i-1).

[0222] In (i-1), the heteroatom-containing unsaturated carbon chaingroup is preferably ethylene or propylene group substituted directlywith an optionally substituted heteroaromatic ring group. With respectto (i-1) and (i-2), examples of “optionally substituted heteroaromaticring group” include thienyl group, furyl group, pyrrolyl group,pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group,thiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group,pyrazinyl group, oxazinyl group, triazinyl group, indolyl group,isoindolyl group, benzimidazolyl group, benzofuranyl group,dihydrobenzofuranyl group, thionaphthenyl group, dihydrothionaphthenylgroup, benzoxazolyl group, quinolyl group, isoquinolyl group,quinolizinyl group, quinoxalinyl group, phthalazinyl group,naphthyridinyl group, acridinyl group, phenoxazinyl group,phenothiazinyl group, purinyl group, xanthinyl group, pteridinyl group,carbazolyl group, dibenzofuranyl group, dibenzothiophenyl group,tetrahydrocarbazolyl group, tetrahydrodibenzofuranyl group,tetrahydrodibenzothiophenyl group and the like. Preferred examplesinclude indolyl group, benzimidazolyl group, benzofuranyl group,benzoxazolyl group, quinolyl group, isoquinolyl group, phenoxazinylgroup, phenothiazinyl group, carbazolyl group, dibenzofuranyl group,dibenzothiophenyl group, tetrahydro-carbazolyl group,tetrahydrodibenzofuranyl group, and tetrahydrodibenzothiophenyl group.More preferred examples include carbazolyl group, dibenzofuranyl group,dibenzothiophenyl group, tetrahydrocarbazolyl group,tetrahydrodibenzofuranyl group, and tetrahydrodibenzothiophenyl group.

[0223] With respect to (i-3) and (i-4), examples of “optionallysubstituted saturated heterocyclic ring group” include tetrahydrofuranylgroup, tetrahydrothienyl group, pyrrolidinyl group, pyrazolonyl group,isoimidazolyl group, imidazolinyl group, imidazolidinyl group,oxazolinyl group, oxazolidinyl group, pyranyl group, thiazinyl group,orthooxazinyl group, oxazinyl group, piperidyl group, piperazinyl group,homopiperazinyl group, dioxanyl group, morpholinyl group, thioxanylgroup, thiomorpholinyl group and the like, with pyrrolidinyl group,piperazinyl group, homopiperazinyl group, dioxanyl group, andmorpholinyl group being preferred.

[0224] In addition, with respect to (i-2) and (i-4), “heteroatomexisting as a substituent” may be oxygen atom, nitrogen atom, or sulfuratom, with oxygen atom and nitrogen atom being more preferred.

[0225] Examples of (j) an optionally substituted heteromonocyclic groupinclude thienyl group, furyl group, pyrrolyl group, pyrazolyl group,imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group,pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group,oxazinyl group, triazinyl group, tetrahydrofuranyl group,tetrahydrothienyl group, pyrrolidinyl group, pyrazolonyl group,isoimidazolyl group, imidazolinyl group, imidazolidinyl group,oxazolinyl group, oxazolidinyl group, pyranyl group, thiazinyl group,orthooxazinyl group, oxazinyl group, piperidyl group, piperazinyl group,homopiperazinyl group, dioxanyl group, morpholinyl group, thioxanylgroup, thiomorpholinyl group and the like, with furyl group, pyrrolylgroup, and pyridyl group being preferred.

[0226] Examples of (k) an optionally substituted heteropolycyclic groupinclude indolyl group, isoindolyl group, benzimidazolyl group,benzofuranyl group, dihydrobenzofuranyl group, thionaphthenyl group,dihydrothionaphthenyl group, benzoxazolyl group, quinolyl group,isoquinolyl group, quinolizinyl group, quinoxalinyl group, phthalazinylgroup, naphthyridinyl group, acridinyl group, phenoxazinyl group,phenothiazinyl group, purinyl group, xanthinyl group, pteridinyl group,carbazolyl group, dibenzofuranyl group, dibenzothiophenyl group,tetrahydrocarbazolyl group, tetrahydrodibenzofuranyl group,tetrahydrodibenzothiophenyl group and the like. Preferred examplesinclude indolyl group, benzimidazolyl group, benzofuranyl group,benzoxazolyl group, quinolyl group, isoquinolyl group, phenoxazinylgroup, phenothiazinyl group, carbazolyl group, dibenzofuranyl group,dibenzothiophenyl group, tetrahydrocarbazolyl group,tetrahydrodibenzofuranyl group, and tetrahydrodibenzothiophenyl group.

[0227] Among the abovementioned groups, R² is preferably:

[0228] (a) an acyl or alkyloxycarbonyl group,

[0229] (b) an optionally substituted straight-chain alkyl group,

[0230] (c) an optionally substituted branched-chain alkyl group,

[0231] (d) an optionally substituted cyclic alkyl group,

[0232] (e) an optionally substituted alkenyl group,

[0233] (f) an optionally substituted aralkyl group,

[0234] (g) an optionally substituted aryl group, or

[0235] (h) a heteroatom-containing saturated carbon chain group;

[0236] more preferably:

[0237] (a) an acyl or alkyloxycarbonyl group,

[0238] (b) an optionally substituted straight-chain alkyl group,

[0239] (c) an optionally substituted branched-chain alkyl group,

[0240] (e) an optionally substituted alkenyl group, or

[0241] (f) an optionally substituted aralkyl group; and

[0242] still more preferably:

[0243] (a) an acyl or alkyloxycarbonyl group, or

[0244] (f) an optionally substituted aralkyl group.

[0245] When (I) R² is (a) an acyl or alkyloxycarbonyl group among theabove groups, R³ represents:

[0246] (Ia) hydrogen,

[0247] (Ib) an optionally substituted straight-chain alkyl group,

[0248] (Ic) an optionally substituted branched-chain alkyl group,

[0249] (Id) an optionally substituted cyclic alkyl group,

[0250] (Ie) an optionally substituted alkenyl group,

[0251] (If) an optionally substituted aralkyl group,

[0252] (Ig) an optionally substituted aryl group,

[0253] (Ih) a heteroatom-containing saturated carbon chain group,

[0254] (Ii) a heteroatom-containing unsaturated carbon chain group,

[0255] (Ij) an optionally substituted heteromonocyclic group,

[0256] (Ik) an optionally substituted heteropolycyclic group, or

[0257] (Ii) a composite group consisting of members suitably selectedfrom any of (Ib) to (Ik); or

[0258] alternatively, when (II) R² is any group other than (a) an acylor alkyloxycarbonyl group among the above groups, R³represents:

[0259] (IIb) an optionally substituted straight-chain alkyl group,

[0260] (IIc) an optionally substituted branched-chain alkyl group,

[0261] (IId) an optionally substituted cyclic alkyl group,

[0262] (IIe) an optionally substituted alkenyl group,

[0263] (IIf) an optionally substituted aralkyl group,

[0264] (IIg) an optionally substituted aryl group,

[0265] (IIh) a heteroatom-containing saturated carbon chain group,

[0266] (IIi) a heteroatom-containing unsaturated carbon chain group,

[0267] (IIj) an optionally substituted heteromonocyclic group,

[0268] (IIk) an optionally substituted heteropolycyclic group, or

[0269] (IIl) a composite group consisting of members suitably selectedfrom any of (IIb) to (IIk); and R² and R³ may be linked to each other toform a heterocyclic group. The substituents set forth above preferablycomprise no acidic functional groups such as phenolic hydroxyl group andcarboxylic acid group.

[0270] With respect to the groups represented by R³, “optionallysubstituted group” referred to in (Ib) to (Ig), (Ij), (Ik), (IIb) to(IIg), (IIj) and (IIk) means a group optionally substituted with fromone to twenty substituents which may be the same or different from eachother, preferably a group optionally substituted with from one to ninesubstituents which may be the same or different from each other, andmore preferably a group optionally substituted with from one to fivesubstituents which may be the same or different from each other.

[0271] The substituents may include alkyl group, alkoxy group, halogen,alkenyl group, nitro group, amino group, acylated amino group,alkylsulfonylated amino group, cyano group, hydroxyl group protectedwith silyl group, aryloxy group and the like. The substituentspreferably comprise no acidic functional groups such as phenolichydroxyl group and carboxylic acid group.

[0272] Examples of (Ib) and (IIb) an optionally substitutedstraight-chain alkyl group include optionally substituted methyl, ethyl,propyl, butyl, pentyl, hexyl groups and the like, with optionallysubstituted methyl and ethyl groups being preferred. Unsubstitutedmethyl and ethyl groups are also preferred.

[0273] Examples of (Ic) and (IIc) an optionally substitutedbranched-chain alkyl group include isopropyl group, isobutyl group,sec-butyl group, tert-butyl group, cyclopropylmethyl group,cyclopropylethyl group, cyclobutylmethyl group, cyclobutylethyl group,cyclopentylmethyl group, cyclopentylethyl group, cyclohexylmethyl group,cyclohexylethyl group and the like, with isopropyl group, tert-butylgroup, cyclopentylmethyl group, and cyclohexylmethyl group beingpreferred.

[0274] Examples of (Id) and (IId) an optionally substituted cyclic alkylgroup include cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, cycloheptyl group and the like, with cyclopropyl groupbeing preferred.

[0275] Examples of (le) and (IIe) an optionally substituted alkenylgroup include allyl group, vinyl group and the like, with allyl groupbeing preferred.

[0276] Examples of (If) and (IIf) an optionally substituted aralkylgroup include benzyl group, p-methoxybenzyl group, p-nitrobenzyl groupand the like, with benzyl group and p-methoxybenzyl group beingpreferred.

[0277] Examples of (Ig) and (IIg) an optionally substituted aryl groupinclude phenyl group, substituted phenyl group, naphthyl group,substituted naphthyl group, anthryl group, substituted anthryl group,phenanthryl group, substituted phenanthryl group, indenyl group,substituted indenyl group, fluorenyl group, substituted fluorenyl groupand the like, with phenyl group, substituted phenyl group, naphthylgroup, and substituted naphthyl group being preferred.

[0278] Examples of (Ih) and (IIh) a heteroatom-containing saturatedcarbon chain group include:

[0279] (h-1) methyl group, ethyl group, propyl group, butyl group,pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butylgroup, tert-butyl group, cyclopropylmethyl group, cyclopropylethylgroup, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethylgroup, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethylgroup and the like which are substituted directly with an optionallysubstituted heteroaromatic ring group;

[0280] (h-2) methyl group, ethyl group, propyl group, butyl group,pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butylgroup, tert-butyl group, cyclopropylmethyl group, cyclopropylethylgroup, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethylgroup, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethylgroup and the like which are substituted with a heteroatom existing as asubstituent on an optionally substituted heteroaromatic ring group;

[0281] (h-3) methyl group, ethyl group, propyl group, butyl group,pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butylgroup, tert-butyl group, cyclopropylmethyl group, cyclopropylethylgroup, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethylgroup, cyclopentylethyl group, cyclohexylmethyl group, cyclohexylethylgroup and the like which are substituted directly with an optionallysubstituted saturated heterocyclic ring group; and

[0282] (h-4) methyl group, ethyl group, propyl group, butyl group,pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butylgroup, tert-butyl group, cyclopropylmethyl group, cyclopropylethylgroup, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethylgroup, cyclopentylethyl group, cyclohexylmethyl group, andcyclohexylethyl group and the like which are substituted with aheteroatom existing as a substituent on an optionally substitutedsaturated heterocyclic ring.

[0283] With respect to (h-1) and (h-2), examples of “optionallysubstituted heteroaromatic ring group” include thienyl group, furylgroup, pyrrolyl group, pyrazolyl group, imidazolyl group, oxazolylgroup, isoxazolyl group, thiazolyl group, pyridyl group, pyridazinylgroup, pyrimidinyl group, pyrazinyl group, oxazinyl group, triazinylgroup, indolyl group, isoindolyl group, benzimidazolyl group,benzofuranyl group, dihydrobenzofuranyl group, thionaphthenyl group,dihydrothionaphthenyl group, benzoxazolyl group, quinolyl group,isoquinolyl group, quinolizinyl group, quinoxalinyl group, phthalazinylgroup, naphthyridinyl group, acridinyl group, phenoxazinyl group,phenothiazinyl group, purinyl group, xanthinyl group, pteridinyl group,carbazolyl group, dibenzofuranyl group, dibenzothiophenyl group,tetrahydrocarbazolyl group, tetrahydrodibenzofuranyl group,tetrahydrodibenzothiophenyl group and the like. Preferred examplesinclude indolyl group, benzimidazolyl group, benzofuranyl group,benzoxazolyl group, quinolyl group, isoquinolyl group, phenoxazinylgroup, phenothiazinyl group, carbazolyl group, dibenzofuranyl group,dibenzothiophenyl group, tetrahydrocarbazolyl group,tetrahydrodibenzofuranyl group, and tetrahydrodibenzothiophenyl group.

[0284] With respect to (h-3) and (h-4), examples of “optionallysubstituted saturated heterocyclic ring group” include tetrahydrofuranylgroup, tetrahydrothienyl group, pyrrolidinyl group, pyrazolonyl group,isoimidazolyl group, imidazolinyl group, imidazolidinyl group,oxazolinyl group, oxazolidinyl group, pyranyl group, thiazinyl group,orthooxazinyl group, oxazinyl group, piperidyl group, piperazinyl group,homopiperazinyl group, dioxanyl group, morpholinyl group, thioxanylgroup, thiomorpholinyl group and the like, with pyrrolidinyl group,piperazinyl group, homopiperazinyl group, dioxanyl group, andmorpholinyl group being preferred.

[0285] With respect to (h-2) and (h-4), “heteroatom existing as asubstituent” may be oxygen atom, nitrogen atom, or sulfur atom, withoxygen atom and nitrogen atom being preferred.

[0286] A heteroatom-containing saturated carbon chain group as (Ih) and(IIh) is preferably selected from (h-1) and (h-2), and more preferablyfrom (h-2).

[0287] In (h-2), the optionally substituted heteroaromatic ring groupmay be particularly preferably carbazolyl group, dibenzofuranyl group,dibenzothiophenyl group, tetrahydrocarbazolyl group,tetrahydrodibenzofuranyl group, or tetrahydrodibenzothiophenyl group. Inaddition, preferred examples of the saturated carbon chain groupsubstituted with a heteroatom existing as a substituent on an optionallysubstituted heteroaromatic ring group include methyl group, ethyl group,propyl group, butyl group, pentyl group, and hexyl group, with methylgroup and ethyl group being more preferred. Most preferably, thesaturated carbon chain group is ethyl group. Further, “heteroatomexisting as a substituent” is preferably oxygen atom or nitrogen atom,and more preferably oxygen atom.

[0288] Examples of (Ii) and (IIi) a heteroatom-containing unsaturatedcarbon chain group include:

[0289] (i-1) ethylene group, propylene group, butenyl group, pentenylgroup, hexenyl group and the like which are substituted directly with anoptionally substituted heteroaromatic ring group;

[0290] (i-2) ethylene group, propylene group, butenyl group, pentenylgroup, hexenyl group and the like which are substituted with aheteroatom existing as a substituent on an optionally substitutedheteroaromatic ring group;

[0291] (i-3) ethylene group, propylene group, butenyl group, pentenylgroup, hexenyl group and the like which are substituted directly with anoptionally substituted saturated heterocyclic ring group; and

[0292] (i-4) ethylene group, propylene group, butenyl group, pentenylgroup, hexenyl group and the like which are substituted with aheteroatom existing as a substituent on an optionally substitutedsaturated heterocyclic ring.

[0293] A heteroatom-containing unsaturated carbon chain group as (Ii)and (IIi) is preferably selected from (i-1) and (i-3), and morepreferably from (i-1).

[0294] In (i-1), the heteroatom-containing unsaturated carbon chaingroup is preferably ethylene or propylene group substituted directlywith an optionally substituted heteroaromatic ring group.

[0295] With respect to (i-1) and (i-2), examples of “optionallysubstituted heteroaromatic ring group” include thienyl group, furylgroup, pyrrolyl group, pyrazolyl group, imidazolyl group, oxazolylgroup, isoxazolyl group, thiazolyl group, pyridyl group, pyridazinylgroup, pyrimidinyl group, pyrazinyl group, oxazinyl group, triazinylgroup, indolyl group, isoindolyl group, benzimidazolyl group,benzofuranyl group, dihydrobenzofuranyl group, thionaphthenyl group,dihydrothionaphthenyl group, benzoxazolyl group, quinolyl group,isoquinolyl group, quinolizinyl group, quinoxalinyl group, phthalazinylgroup, naphthyridinyl group, acridinyl group, phenoxazinyl group,phenothiazinyl group, purinyl group, xanthinyl group, pteridinyl group,carbazolyl group, dibenzofuranyl group, dibenzothiophenyl group,tetrahydrocarbazolyl group, tetrahydrodibenzofuranyl group,tetrahydrodibenzothiophenyl group and the like. Preferred examples of“optionally substituted heteroaromatic ring group” include indolylgroup, benzimidazolyl group, benzofuranyl group, benzoxazolyl group,quinolyl group, isoquinolyl group, phenoxazinyl group, phenothiazinylgroup, carbazolyl group, dibenzofuranyl group, dibenzothiophenyl group,tetrahydrocarbazolyl group, tetrahydrodibenzofuranyl group, andtetrahydrodibenzothiophenyl group. More preferred examples includecarbazolyl group, dibenzofuranyl group, dibenzothiophenyl group,tetrahydrocarbazolyl group, tetrahydrodibenzofuranyl group, andtetrahydro-dibenzothiophenyl group.

[0296] With respect to (i-3) and (i-4), examples of “optionallysubstituted saturated heterocyclic ring group” include tetrahydrofuranylgroup, tetrahydrothienyl group, pyrrolidinyl group, pyrazolonyl group,isoimidazolyl group, imidazolinyl group, imidazolidinyl group,oxazolinyl group, oxazolidinyl group, pyranyl group, thiazinyl group,orthooxazinyl group, oxazinyl group, piperidyl group, piperazinyl group,homopiperazinyl group, dioxanyl group, morpholinyl group, thioxanylgroup, thiomorpholinyl group and the like, with pyrrolidinyl group,piperazinyl group, homopiperazinyl group, dioxanyl group, andmorpholinyl group being preferred.

[0297] With respect to (i-2) and (i-4), “heteroatom existing as asubstituent” may be oxygen atom, nitrogen atom, or sulfur atom, withoxygen atom and nitrogen atom being preferred.

[0298] Examples of (Ij) and (IIj) “optionally substitutedheteromonocyclic group” include thienyl group, furyl group, pyrrolylgroup, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolylgroup, thiazolyl group, pyridyl group, pyridazinyl group, pyrimidinylgroup, pyrazinyl group, oxazinyl group, triazinyl group,tetrahydrofuranyl group, tetrahydrothienyl group, pyrrolidinyl group,pyrazolonyl group, isoimidazolyl group, imidazolinyl group,imidazolidinyl group, oxazolinyl group, oxazolidinyl group, pyranylgroup, thiazinyl group, orthooxazinyl group, oxazinyl group, piperidylgroup, piperazinyl group, homopiperazinyl group, dioxanyl group,morpholinyl group, thioxanyl group, thiomorpholinyl group and the like,with furyl group, pyrrolyl group, and pyridyl group being preferred.

[0299] Examples of (Ik) and (IIk) “optionally substitutedheteropolycyclic group” include indolyl group, isoindolyl group,benzimidazolyl group, benzofuranyl group, dihydrobenzofuranyl group,thionaphthenyl group, dihydrothionaphthenyl group, benzoxazolyl group,quinolyl group, isoquinolyl group, quinolizinyl group, quinoxalinylgroup, phthalazinyl group, naphthyridinyl group, acridinyl group,phenoxazinyl group, phenothiazinyl group, purinyl group, xanthinylgroup, pteridinyl group, carbazolyl group, dibenzofuranyl group,dibenzothiophenyl group, tetrahydrocarbazolyl group,tetrahydrodibenzofuranyl group, tetrahydrodibenzothiophenyl group andthe like. Further, preferred examples include indolyl group,benzimidazolyl group, benzofuranyl group, benzoxazolyl group, quinolylgroup, isoquinolyl group, phenoxazinyl group, phenothiazinyl group,carbazolyl group, dibenzofuranyl group, dibenzothiophenyl group,tetrahydro-carbazolyl group, tetrahydrodibenzofuranyl group, andtetrahydro-dibenzothiophenyl group.

[0300] With respect to (IIl), examples of nitrogen atom-containingheterocyclic ring group formed by R² and R³ which are bonded to eachother include aziridine ring, azetidine ring, pyrrole ring, pyrrolidinering, pyrazole ring, pyrazolone ring, imidazole ring, isoimidazole ring,imidazoline ring, imidazolidine ring, oxazolidine ring, piperidine ring,piperazine ring, homopiperazine ring, morpholine ring, thiomorpholinering, tetrahydroquinoline ring, tetrahydroisoquinoline ring, indolering, isoindole ring, benzimidazole ring, phenoxazine ring,phenothiazine ring, purine ring, xanthine ring, carbazole ring,tetrahydrocarbazole ring and the like. Further, preferred examplesinclude aziridine ring, pyrrolidine ring, piperidine ring, piperazinering, homopiperazine ring, morpholine ring, and thiomorpholine ring.

[0301] Among the abovementioned groups, R³ is preferably:

[0302] (a) hydrogen,

[0303] (b) an optionally substituted straight-chain alkyl group,

[0304] (c) an optionally substituted branched-chain alkyl group,

[0305] (d) an optionally substituted cyclic alkyl group,

[0306] (e) an optionally substituted alkenyl group,

[0307] (f) an optionally substituted aralkyl group,

[0308] (g) an optionally substituted aryl group,

[0309] (h) a heteroatom-containing saturated carbon chain group, or

[0310] (i) a heteroatom-containing unsaturated carbon chain group;

[0311] more preferably:

[0312] (b) an optionally substituted straight-chain alkyl group,

[0313] (c) an optionally substituted branched-chain alkyl group,

[0314] (d) an optionally substituted cyclic alkyl group,

[0315] (e) an optionally substituted alkenyl group,

[0316] (f) an optionally substituted aralkyl group,

[0317] (g) an optionally substituted aryl group,

[0318] (h) a heteroatom-containing saturated carbon chain group, or

[0319] (i) a heteroatom-containing unsaturated carbon chain group;

[0320] still more preferably:

[0321] (b) an optionally substituted straight-chain alkyl group,

[0322] (f) an optionally substituted aralkyl group, or

[0323] (h) a heteroatom-containing saturated carbon chain group; and

[0324] particularly preferably:

[0325] (h) a heteroatom-containing saturated carbon chain group.

[0326] Compounds represented by the general formula (1) set forth abovewherein A is CH₂NR²R³, and R² is neither an acyl group nor analkyloxycarbonyl group, which are ketone compounds having an amine typenitrogenous functional group, may be used not only in the form of freeamine but also as a salt with commonly used mineral or organic acid. Thecommonly used mineral acid is not limited as long as it has no oxidizingproperty. Examples thereof include hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid and the like, with hydrochloric acid andhydrobromic acid being more preferred. The commonly used organic acid isnot limited as long as it has no oxidizing property, and may be acarboxylic acid, such as formic acid, acetic acid, butyric acid, ortrifluoroacetic acid, with acetic acid and trifluoroacetic acid beingmore preferred.

[0327] Among ketone compounds represented by the general formula (1),compounds of the formula (1) in which n is 0 and A is CH₂NR²R³ includecompounds useful as an important intermediate for the preparation ofmedicaments which are described in WO 97/25311 and WO 99/01431 as beingvery useful for treating and preventing diabetes, obesity,hyperlipidemia and the like. Such compounds may be specified as follows.

[0328] That is, R¹ represents a substituted phenyl group, such as3-aminophenyl group, 3-nitrophenyl group, 3-[(benzyl)(methylsulfonyl)amino]phenyl group, 4-chloro-3-aminophenyl group,4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-chloro-3-nitrophenyl group, 4-bromo-3-aminophenyl group,4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-bromo-3-nitrophenyl group, 4-benzyloxy-3-nitrophenyl group,4-benzyloxy-3-aminophenyl group,4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl group, or4-benzyloxy-3-[(hydroxy)methyl]phenyl group. R¹ may be preferably4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl group,3-[(benzyl)-(methylsulfonyl)amino]phenyl group, or4-benzyloxy-3-[(benzyl)-(methylsulfonyl)amino]phenyl group. Further, R²represents an amino-protecting group which can be removed under a mildcondition. Specific examples thereof include an acyl group, such asacetyl group, propionyl group, butyryl group, pentanoyl group, hexanoylgroup, trifluoroacetyl group, pivaloyl group, benzoyl group,4-methoxybenzoyl group, 2,4,6-trimethylbenzoyl group, or naphthoylgroup; a carbamate type protecting group, such as tert-butoxycarbonylgroup, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, or2,2,2-trichloroethoxycarbonyl group; and an aralkyl group, such asbenzyl group, p-methoxybenzyl group, or p-nitrobenzyl group, withbenzoyl group and benzyl group being preferred. Further, R³ representsan ethyl group which is bonded at its end to a fused tricyclic ringgroup via an oxygen atom. Specific examples thereof include2-(dibenzofuran-3-yloxy)ethyl group, 2-(dibenzo-thiophen-3-yloxy)ethylgroup, 2-(9H-carbazol-2-yloxy)ethyl group,2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl group,2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl group, and2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl group, with2-(9H-carbazol-2-yloxy)ethyl group being preferred.

[0329] Particularly preferred examples of the ketone compounds havingthe abovementioned substituents are set forth below. That is, suchparticularly preferred examples may be the compounds having a benzylgroup as R², such as:

[0330]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0331] 1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-,[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0332]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0333]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]-benzylamino]ethanone;

[0334]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0335]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0336]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0337]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0338]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0339]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]-benzylamino]ethanone;

[0340]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0341]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0342]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0343]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0344]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0345]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]-benzylamino]ethanone;

[0346]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0347]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0348]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0349]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0350]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0351]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]-ethanone;

[0352]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0353]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0354]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0355]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0356]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0357]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]-ethanone;

[0358]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0359]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0360]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0361]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0362]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0363]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-dibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0364]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0365]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0366]1-(4-chloro-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0367]1-(4-chloro-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzylamino]ethanone;

[0368]1-(4-chloro-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0369]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0370]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0371]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0372]1-(4-bromo-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)-ethyl]benzylamino]ethanone

[0373]1-(4-bromo-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzylamino]ethanone;

[0374]1-(4-bromo-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0375]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0376]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0377]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0378]1-(3-aminophenyl)-2-[[2,-(dibenzothiophen-3-yloxy)ethyl]-benzylamino]ethanone;

[0379]1-(3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]-benzylamino]ethanone;

[0380]1-(3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]-benzylamino]ethanone;

[0381]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0382]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0383]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0384]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0385]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0386]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0387]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0388]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0389]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0390]1-(4-chloro-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0391]1-(4-chloro-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzylamino]ethanone;

[0392]1-(4-chloro-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0393]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0394]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0395]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0396]1-(4-bromo-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)-ethyl]benzylamino]ethanone;

[0397]1-(4-bromo-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzylamino]ethanone;

[0398]1-(4-bromo-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0399]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-dibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0400]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0401]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0402] 1-(3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]-benzylamino]ethanone;

[0403]1-(3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]-benzylamino]ethanone;

[0404]1-(3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]-benzylamino]ethanone;

[0405]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0406]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;and

[0407]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;and acceptable salts thereof, such as hydrochloride, acetate,hydrobromide, and trifluoroacetate.

[0408] Further, the compounds having a benzoyl group as R² may be alsoparticularly preferred. Specific examples thereof include:

[0409]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0410]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0411]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0412]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0413]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0414]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0415]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0416]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0417]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0418]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0419]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0420]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0421]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0422]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0423]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0424]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0425]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0426]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0427]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0428]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0429]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0430]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]-ethanone;

[0431]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]-ethanone;

[0432]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]-ethanone;

[0433]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0434]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0435]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0436]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0437]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0438]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0439]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0440]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0441]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0442]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0443]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0444]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0445]1-(4-chloro-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0446]1-(4-chloro-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzoylamino]ethanone;

[0447]1-(4-chloro-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0448]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0449]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0450]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0451]1-(4-bromo-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)-ethyl]benzoylamino]ethanone;

[0452]1-(4-bromo-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzoylamino]ethanone;

[0453]1-(4-bromo-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0454]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0455]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0456]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0457]1-(3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]-benzoylamino]ethanone;

[0458]1-(3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]-benzoylamino]ethanone;

[0459]1-(3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]-benzoylamino]ethanone;

[0460]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0461]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]-ethanone;

[0462]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0463]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0464]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0465]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0466]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0467]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0468]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0469]1-(4-chloro-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0470]1-(4-chloro-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzoylamino]ethanone;

[0471]1-(4-chloro-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0472]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0473]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0474]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0475]1-(4-bromo-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)-ethyl]benzoylamino]ethanone;

[0476]1-(4-bromo-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzoylamino]ethanone;

[0477]1-(4-bromo-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0478]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0479]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrdibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0480]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0481]1-(3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]-benzoylamino]ethanone;

[0482]1-(3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]-benzoylamino]ethanone;

[0483]1-(3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]-benzoylamino]ethanone;

[0484]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0485]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;and

[0486]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone.

[0487] Ketone compounds having a nitrogenous or oxygenic functionalgroup at any of the α-, β- and γ-positions which are the reactionsubstrates represented by the general formula (1) may be synthesized asfollows.

[0488] A process for the preparation of compounds of the general formula(1) in which A is CH₂NR² R³ and R² is neither an acyl group nor analkyloxycarbonyl group, or ketone compounds having an amine typenitrogenous functional group, may comprising condense a leavinggroup-containing ketone compound [4-a] with a secondary amine compound[4-b] as indicated in the reaction scheme (4):

[0489] wherein R¹, R³ and n are as defined above; R² is neither an acylgroup nor an alkyloxycarbonyl group; and

[0490] B² represents

[0491] (a) halogen, such as chlorine, bromine or iodine;

[0492] (b) a sulfonate group, such as mesylate or tosylate group; or

[0493] (c) a leaving group, such as quaternary ammonium salt.

[0494] This condensation reaction may be carried out by methodsdescribed in literatures [for example, as regards synthesis ofα-aminoketone compounds: Larsen, A. A., et al., Journal of MedicinalChemistry, 10, p. 462 (1967), and Larsen, A. A., et al., Journal ofMedicinal Chemistry, 9, pp. 88-97 (1966); as regards synthesis ofβ-aminoketone compounds: Maxwell, C. E., Organic Synthesis CollectiveVol. 3, pp. 305-306 (1955); as regards synthesis of γ-aminoketonecompounds: Yevich, J. P. et al., Journal of Medicinal Chemistry, 35, pp.4516-4525 (1992)]. Generally, the process may be carried out in thepresence of aromatic hydrocarbon type solvent (such as toluene orxylene), ether type solvent (such as diethyl ether, tetrahydrofuran(THF), 1,4-dioxane, diisopropyl ether (IPE), or tert-butyl methyl ether(MTBE)), polar solvent (such as acetonitrile, acetone, methyl ethylketone (MEK), dimethylformamide (DMF), dimethylacetamide (DMA),N-methylpyrrolidone (NMP), or dimethylsulfoxide (DMSO)), or alcohol typesolvent (such as methanol, ethanol, 2-propanol, 1-butanol, or2-butanol). The process may be also carried out in the absence of theabovementioned solvents when [4-b] is used in an excess amount and alsoacts as a solvent.

[0495] This reaction is generally carried out using a base catalyst asan acid scavenger, such as alkali metal salt (such as potassiumcarbonate or sodium carbonate) or organic base (such as triethylamine,Hunig's base, pyridine or collidine), in an amount of from 1 to 10 mol,preferably from 1 to 5 mol, more preferably from 1 to 2 mol for 1 mol ofa leaving group B The reaction may be also carried out without theseacid scavengers, however, when [4-b] is used in an excess amount.Further, when the leaving group B² is chlorine or bromine, the reactiontime can be shortened by adding iodide such as sodium iodide orpotassium iodide as a halogen exchange catalyst in an amount of from0.01 to 10 times by mole, preferably from 0.1 to 0.3 times by mole. Thisreaction can be generally completed at temperatures ranging from −20° C.to 200° C. for from 1 to 48 hours, and is more preferably carried out attemperatures ranging from 20° C. to 100° C. for from 1 to 24 hours.

[0496] Alternatively, as indicated in the reaction scheme (5):

[0497] wherein R¹, R², R³, n and B² are as defined for the reactionscheme (4), this condensation reaction may be a process comprisingheating a leaving group B²-containing ketone compound at temperaturesranging from 80° C. to 100° C. in the presence of an acid catalyst suchas p-toluenesulfonic acid in 1,2-ethanediol to protect the carbonylgroup of the ketone compound as ketal; condensing the protected ketonecompound with a secondary amine compound [4-b]; and then deprotectingthe ketal group of [5-b] to give a salt of desired aminoketone compound[4-c]. This reaction of [5-a] with [4-b] may be carried out according tothe procedure indicated in the reaction scheme (4). Theketal-deprotecting method is not limited as long as it is a methodcommonly used. For example, the deprotection may be carried out withgood yield by using from 0.1 to 10 times by mole, preferably 0.1 to 2times by mole of dilute hydrochloric acid in THF as a solvent attemperatures ranging from 20° C. to 40° C. for from 1 to 24 hours.Further, aminoketone compounds generated may be simultaneouslysolidified as hydrochloride salt and may be also easily purified byrecrystallization.

[0498] Compounds of the general formula (1) in which A is CH₂NR²R³ andR² is an acyl group or an alkyloxycarbonyl group, or ketone compoundshaving an amide type nitrogenous functional group, may be synthesized byknown processes described in literatures [for example, Ikezaki, et al.,YAKUGAKU ZASSHI, 106(1), pp. 80-89 (1986); and Takayuki Kawaguchi, etal., Chemical & Pharmaceutical Bulletin, 41(4), pp. 639-642 (1993)].That is, as indicated in the reaction scheme (6):

[0499] wherein R¹, R³, n and B² are as defined above;

[0500] R¹⁷ represents

[0501] (a) an alkyl group, or

[0502] (b) an alkoxy group; and

[0503] B³ represents

[0504] (a) halogen, such as chlorine or bromine,

[0505] (b) a carboxylic ester, such as formyloxy group or acetoxy group,or

[0506] (c) a leaving group such as mesylate, tosylate ortrifluoromethanesulfonate group,

[0507] a ketone compound having an amide type nitrogenous functionalgroup [6-d] may be synthesized by condensing a leaving groupB²-containing ketone compound [4-a] with a primary amine compound [6-a]to give a secondary aminoketone compound [6-b]; and protecting the aminogroup of [6-b] with an acylating or alkyloxycarbonylating agent [6-c].

[0508] Alternatively, as indicated in the reaction scheme (7):

[0509] wherein R¹, R¹⁷, R³, n, B² and B³ are as defined above, a ketalcompound containing an amide type nitrogenous functional group [7-b] maybe synthesized by condensing a leaving group B²-containing ketalcompound [5-a] with a primary amine compound [6-a] to give a secondaryaminoketal compound [7-a]; and protecting the secondary amino group withan acylating or alkyloxycarbonylating agent [6-c]. Alternative processmay be a process comprising deprotecting [7-b] with hydrochloric acid orthe like to synthesize [6-d]. This condensation reaction of [4-a] or[5-a] with primary amine compound [6-a] may be generally carried out inthe presence of aromatic hydrocarbon type solvent (such as toluene orxylene), ether type solvent (such as diethyl ether, tetrahydrofuran(THF), 1,4-dioxane, diisopropyl ether (IPE), or tert-butyl methyl ether(MTBE)), polar solvent (such as acetonitrile, acetone, methyl ethylketone (MEK), dimethylformamide (DMF), dimethylacetamide (DMA),N-methylpyrrolidone (NMP), or dimethylsulfoxide (DMSO)), or alcohol typesolvent (such as methanol, ethanol, 2-propanol, 1-butanol, or2-butanol). The condensation reaction may also be carried out in theabsence of the abovementioned solvent when [6-a] is used in an excessamount and also acts as a solvent.

[0510] According to this condensation reaction, a base catalyst as anacid scavenger, such as alkali metal salt (such as potassium carbonateor sodium carbonate) or organic base (such as triethyl-amine, Hunig'sbase, pyridine or collidine) may be used in an amount of from 1 to 10mol, preferably from 1 to 5 mol, more preferably from 1 to 2 mol for 1mol of the leaving group B². The process using a large excess amount of[6-a] in the absence of these acid scavengers may also be preferred inthe viewpoint of inhibiting generating the dialkylated form. Further,when the leaving group B² is chlorine or bromine, the reaction time canbe shortened by adding iodide such as sodium iodide or potassium iodideas a halogen exchange catalyst in an amount of from 0.01 to 10 times bymole, preferably from 0.1 to 0.3 times by mole. This reaction can begenerally completed at temperatures ranging from −20° C. to 100° C. forfrom 0.1 to 48 hours, and may be more preferably carried out attemperatures ranging from 20° C. to 50° C. for from 0.1 to 1 hour. Withrespect to this condensation reaction, using a biphasic solvent systemconsisting of water and organic solvent is possible and may beparticularly preferred. That is, the process for preparing the secondaryaminoketone compound [6-b] may be a process comprising dissolving [6-a]in an amount of from 1 to 5 times by mole, preferably from 3 to 5 timesby mole, more preferably from 3 to 3.5 times by mole, based on theleaving group B² in a water-immiscible solvent such as toluene at arelatively high concentration of from 0.1 to 5 mol/L, preferably from0.5 to 2 mol/L; adding as an acid scavenger, from 1 to 5 L, preferablyfrom 1 to 1.5 L of an aqueous sodium hydroxide solution having aconcentration of from 5 to 50 w/v %, preferably from 10 to 20 w/v %, for1 mol of the leaving group B²; adding portionwise [4-a] with vigorousstirring at temperatures ranging from 0° C. to 10° C., preferably from2° C. to 7° C.; and, while maintaining the reaction temperature in therange of from 2° C. to 7° C., allowing the reaction to proceed for from0.5 to 5 hours, preferably from 1 to 3 hours.

[0511] As occasion demands, a salt of [6-b] may be synthesized by using,for example, 10 w/v % hydrochloric acid at temperatures ranging from 0°C. to 50° C., preferably from 10° C. to 30° C., to form hydrochloridesalt. Then, R² or an acyl or alkyloxycarbonyl group represented byR¹⁷C(═O) may be introduced by the conventional method described in theliterature accepted in the art (Greene, T. W., et al., Protective Groupsin Organic Synthesis (Wiley-Interscience Publication)). For example, abenzoyl group may be introduced into the secondary aminoketone compound[6-b] by treating the aminoketone compound with benzoyl chloride in anamount of from 1 to 3 mol, preferably from 1 to 1.2 mol for 1 mol of theaminoketone compound in a solvent such as dichloroethane or THF in thepresence of an acid scavenger such as sodium hydrogencarbonate attemperatures ranging from 0° C. to 30° C.

[0512] Next, when A of the general formula (1) is OR⁴ and R⁴ isSiR⁵R⁶R⁷, as indicated in the reaction scheme (8):

[0513] wherein R¹, B², R⁵, R⁶, R⁷ and n are as defined above, asilyloxyketone compound [8-c] may be synthesized by treating [4-a] or[5-a] with alkali such as NaOH or KOH; in case of [5-a], deprotectingketal by an acid treatment; and reacting the thus obtainedhydroxylketone compound [8-a] with B²-SiR⁵R⁶R⁷ [8-b] which is asililating agent. This sililating reaction may be carried out by theconventional method for protecting a hydroxyl group with silyl describedin the literature accepted in the art (Greene, T. W., et al., ProtectiveGroups in Organic Synthesis (Wiley-Interscience Publication)).

[0514] Specifically, the process may be a process comprising dissolving[8-a] in a solvent such as THF, dichloromethane or DMF at aconcentration of from 0.1 to 10 mol/L, preferably from 1 to 5 mol/L;adding an organic base such as imidazole, triethylamine or pyridine asan acid scavenger, preferably adding imidazole in an amount of from 1.0to 1.5 times by mole, more preferably from 1.1 to 1.3 times by molebased on the sililating agent; and reacting [8-a] with a sililatingagent such as tert-butyldiphenyl-chlorosilane in an amount of from 1.05to 1.2 times by mole at temperatures ranging from 0° C. to 30° C. forfrom 0.5 to 12 hours.

[0515] Further, as indicated in the reaction scheme (9):

[0516] wherein R¹, B², R⁴ and n are as defined above, a ketone compoundhaving an ether type oxygenic functional group may be synthesized byreacting [4-a] with an alcohol, phenol or silanol compound [9-a]represented by HOR⁴. An alternative process using [5-a] may be also usedto synthesize an ether linkage-containing ketal compound [9-c]. Theselective deprotection of ketal group afford the ketone compound [9-d].Generally, this substitution reaction between HOR⁴ [9-a] and the leavinggroup B² may be carried out using [9-a] in an amount of from 1 to 10mol, preferably from 1.1 to 2.0 mol for 1 mol of the leaving group B² inaromatic hydrocarbon solvent (such as toluene or xylene), ether typesolvent (such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,diisopropyl ether (IPE), or tert-butyl methyl ether (MTBE)), or polarsolvent (such as acetonitrile, acetone, methyl ethyl ketone (MEK),dimethyl-formamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone(NMP), or dimethylsulfoxide (DMSO)).

[0517] Further, when [9-a] is a lower alcohol such as methanol, ethanol,2-propanol, 1-butanol or 2-butanol, it may be also preferred to use[9-a] per se in a large excess amount as a solvent. According to thissubstitution reaction, a base catalyst, such as alkali metal salt (suchas sodium hydroxide, potassium carbonate or sodium carbonate) or anorganic base (such as triethylamine, Hunig's base, pyridine orcollidine) may be used as an acid scavenger in an amount of from 1 to 10mol, preferably from 1 to 5 mol, more preferably from 1 to 2 mol for 1mol of the leaving group B². It may be also preferred to previouslyconvert the hydroxyl group of HOR⁴ [9-a] into its activated saltrepresented by M⁺⁻OR⁴ [9-b] wherein M⁺ represents a monovalent metal ionor quaternary ammonium ion, with a strong base such as a metal hydride(such as sodium hydride) or tetrabutylammonium hydroxide; and reacting[4-a] with the activated salt at relatively low temperatures rangingfrom −20° C. to 5° C. Further, when the leaving group B² is chlorine orbromine, the reaction time can be shortened by adding iodide as ahalogen exchange catalyst in an amount of from 0.01 to 10 times by mole,preferably from 0.1 to 0.3 times by mole as set forth above. Thisreaction can be generally completed at temperatures ranging from −20° C.to 100° C. for from 0.1 to 48 hours, and may be more preferablycompleted at temperatures ranging from 20° C. to 50° C. for from 0.1 to1 hour.

[0518] When A of the general formula (1) is CH(OR¹⁵)₂, the process forsynthesizing a ketal type oxygenic functional group-containing ketonecompound wherein n is 0, 1 or 2 may vary depending the numerical valueof n.

[0519] When n is 0, as indicated in the reaction scheme (10):

[0520] wherein R¹ and R¹⁵ are as defined above, the ketone compounds ofinterest may be synthesized by directly using a glyoxal compound [10-a]according to the known methods described in the literatures (Evans, etal., J. Chem. Soc., pp. 3324-3328 (1955); Henery-Logan, et al., Chem.Commun., 130 (1968); Trost, B. M., et al., J. Org. Chem., 45(14), pp.2741-2746 (1980)). Alternatively, [10-a] obtained by oxidizing a varietyof methyl ethyl ketone compounds [10-d] with 47% hydrobromic acid anddimethylsulfoxide according to the known methods described in theliteratures (Bruce, M. J., et al., J. Chem. Soc. Perkin Trans.1, 14, pp.1789-1796 (1995); and Tanaka, Yasuhiro, et al., Chem. Pharm. Bull.,44(5), pp. 885-891 (1996)) may be also used as the glyoxal compound setforth above. Specifically, an α-ketalketone compound [10-c] may besynthesized by heating/dehydrating a mixture of [10-a] with an alcoholcompound [10-b] represented by R¹⁵OH or a diol compound such as1,2-ethanediol or 1,3-propanediol in an amount of from 1 to 10 times bymole, preferably from 1 to 2 times by mole, in a solvent such as toluenein the presence of an acid catalyst such as hydrochloric acid, sulfuricacid or p-toluenesulfonic acid. Further, when the known method describedin the literature (Chan, T. H., et al., Synthesis, 3, pp. 203-205(1983))is used, [10-c] may be also synthesized by a process under a relativelymild condition wherein the process comprises reacting [10-a] with [10-b]in the presence of a Lewis acid catalyst such as trimethylsilyl chlorideat room temperature for from 12 to 24 hours. An alternative processwhich does not use [10-a] may be a more abbreviated process for-directlysynthesizing [10-c] from a variety of methylketone compounds [10-d]according to the known method described in the literature (Tiecco, M.,et al., J. Org. Chem., 55(15), pp. 4523-4528 (1990)) wherein the processcomprises treating a methylketone compound [10-d] with ammoniumperoxydisulfate and diphenyldiselenide in the presence of [10-b] forfrom 0.5 to 2 hours.

[0521] Next, when n is 1, as indicated in the reaction scheme (11):

[0522] wherein R¹ and R¹⁵ are as defined above, a β-ketalketone compound[11-c] may be synthesized from a silyl enol ether [11-a] by the knownmethods described in the literatures (Makin, S. M., et al., J. Org.Chem. USSR (Engl. Transl.), 17(4), pp. 630-634 (1981); and Sakurai,Hideki, et al., Bull. Chem. Soc. Jpn., 56(10), pp. 3195-3196 (1983)).That is, the β-ketalketone compound [11-c] may be synthesized byreacting the silyl enol ether [11-a] with trialkoxymethane [11-b] suchas trimethoxymethane in an aprotic solvent such as ethyl acetate ordichloromethane in the presence of a strong Lewis acid catalyst such asZnCl₂ or trimethyliodosilane at temperatures ranging from −78° C. to 25°C. for from 1 to 3 hours. The silyl enol ether [11-a] may be easilyprepared by treating a variety of methylketone compounds [10-d] with anorganic base such as triethylamine or LDA (lithium diisopropylamide) inan amount of from 1 to 1.1 times by mole and trimethylchlorosilane in anamount of from 1 to 1.1 times by mole.

[0523] Further, when n is 2, as indicated in the reaction scheme (12):

[0524] wherein R¹ and R¹⁵ are as defined above, and B² representschlorine or bromine, a γ-ketalketone compound [12-c] may be synthesizedaccording to the known method described in the literature (Kirrmann, etal., Bull. Soc. Chim. Fr., <5>2, p. 2150 (1935)) by reacting acommercially available γ-ketalnitrile compound [12-a] with a Grignardreagent [12-b] in an amount of from 1.0 to 1.05 times by mole in anether type solvent such as diethyl ether or THF at relatively lowtemperatures ranging from −78° C. to 0° C. for from 1 to 6 hoursfollowed by a hydrolysis reaction at normal temperature for from 1 to 2hours. Further, [12-c] may be also synthesized according to the knownmethod described in the literature (Barluenga, J., et al., J. Chem. Soc.Perkin Trans.1, pp. 3113-3118 (1988)) by reacting nitrile [12-d] or acidchloride [12-f] with a nucleophilic reagent (prepared from γ-ketalhalide [12-e] and an organolithium compound such as lithiumnaphthalenide) in an amount of from 1.0 to 1.1 times by mole in an ethertype anhydrous solvent such as diethyl ether or THF at low temperaturesranging from −78° C. to −20° C. followed by a hydrolysis reaction atnormal temperature for from 1 to 2 hours.

[0525] Likewise, [12-c] may be also synthesized according to the knownmethod described in the literature (Watanabe, Masami, et al., J. Chem.Soc. Perkin Trans.1, 21, pp. 3125-3128 (1994)) by subjecting nitrile[12-d] or acid chloride [12-f] to a nucleophilic reaction with a γ-ketalGrignard reagent [12-g] (easily prepared by a treatment of [12-e] withmagnesium metal in diethyl ether) in an amount of from 1.0 to 1.1 timesby mole in an ether type anhydrous solvent such as diethyl ether or THFat low temperatures ranging from −78° C. to −20° C. followed by ahydrolysis reaction at normal temperature for from 1 to 2 hours.

[0526] The ruthenium/optically active bidentate phosphine/diaminecomplex to be used in the present invention is represented by thegeneral formula (2). In the formula, m represents an integer of from 0to 2, with 0 being preferred.

[0527] X and Y may be the same or different and may be bonded to theruthenium via covalent bond or ionic bond. They specifically represents:

[0528] (a) hydrogen,

[0529] (b) halogen,

[0530] (c) an alkoxy group,

[0531] (d) a carboxyl group, or

[0532] (e) other anion group.

[0533] (f) other anion group may be selected from a variety of aniongroups and examples thereof include [BH₄]⁻ and [BF₄]⁻. X and Y are morepreferably hydrogen, halogen or [BH₄]⁻.

[0534] The ruthenium/optically active bidentate phosphine/diaminecomplex comprises in the molecule an optically active bidentatephosphine ligand and a diamine ligand. The optically active bidentatephosphine ligand is represented by the general formula (13):

[0535] wherein R⁸ represents:

[0536] (a) hydrogen,

[0537] (b) a lower alkyl group,

[0538] (c) a lower alkoxy group, or

[0539] (d) N(R¹⁴)₂ wherein R¹⁴ represents a lower alkyl group;

[0540] R⁹ represents:

[0541] (a) hydrogen,

[0542] (b) a lower alkyl group, or

[0543] (c) a lower alkoxy group;

[0544] R¹⁰ represents:

[0545] (a) a lower alkyl group, or

[0546] (b) a lower alkoxy group;

[0547] the dashed line linking one R¹⁰ to the other R¹⁰ means that oneR¹⁰ may be bonded to the other R¹⁰ via an oxygen atom;

[0548] one dashed line linking R⁹ to R¹⁰, and the other dashed linelinking R⁹ to R¹⁰ independently mean that each pair of R⁹ and R¹⁰ takentogether with the benzene ring to which they are attached may form anoptionally substituted tetralin ring, an optionally substitutednaphthalene ring, or an optionally substituted 1,3-benzodioxole ring;

[0549] Ar¹ and Ar² may be the same or different and independentlyrepresent a phenyl group substituted with from zero to five substituentsselected from straight-chain or branched-chain lower alkyl group,halogen or lower alkoxy group.

[0550] In the formula (13), R⁸ represents

[0551] (a) hydrogen,

[0552] (b) a lower alkyl group,

[0553] (c) a lower alkoxy group, or

[0554] (d) N(R¹⁴)₂, wherein R¹⁴ represents a lower alkyl group.

[0555] As R⁸,

[0556] (b) the lower alkyl group may be methyl group, ethyl group,isopropyl group, tert-butyl group, or trifluoromethyl group, with methylgroup and trifluoromethyl group being preferred;

[0557] (c) the lower alkoxy group may be methoxy group, ethoxy group,isopropoxy group, tert-butoxy group, or trifluoromethoxy group, withmethoxy group and trifluoromethoxy group being preferred; and

[0558] (d) R¹⁴ in N(R¹⁴)₂ may be methyl group, ethyl group or isopropylgroup, with methyl group being preferred.

[0559] Among the above, R⁸ is preferably

[0560] (a) hydrogen,

[0561] (b) a lower alkyl group, or

[0562] (c) a lower alkoxy group; and

[0563] more preferably

[0564] (a) hydrogen, or

[0565] (b) a lower alkyl group.

[0566] R⁹ represents:

[0567] (a) hydrogen,

[0568] (b) a lower alkyl group, or

[0569] (c) a lower alkoxy group; or alternatively

[0570] one dashed line linking R⁹ to R¹⁰, and the other dashed linelinking R⁹ to R¹⁰ independently mean that each pair of R⁹ and R¹⁰ takentogether with the benzene ring to which they are attached may form:

[0571] (a) a tetralin ring optionally substituted with R⁸,

[0572] (b) a naphthalene ring optionally substituted with R⁸, or

[0573] (c) a 1,3-benzodioxole ring optionally substituted with R⁸.

[0574] R¹⁰ represents:

[0575] (a) a lower alkyl group, or

[0576] (b) a lower alkoxy group; or alternatively,

[0577] like the above, one dashed line linking R⁹ to R¹⁰, and the otherdashed line linking R⁹ to R¹⁰ independently mean that each pair of R⁹and R¹⁰ taken together with the benzene ring to which they are attachedmay form:

[0578] (a) a tetralin ring optionally substituted with R⁸,

[0579] (b) a naphthalene ring optionally substituted with R⁸, or

[0580] (c) a 1,3-benzodioxole ring optionally substituted with R⁸.

[0581] As R⁹,

[0582] (b) the lower alkyl group may be methyl group, ethyl group,isopropyl group, tert-butyl group, or trifluoromethyl group, with methylgroup and trifluoromethyl group being preferred; and

[0583] (c) the lower alkoxy group may be methoxy group, ethoxy group,isopropoxy group, tert-butoxy group, or trifluoromethoxy group, withmethoxy group and trifluoromethoxy group being preferred.

[0584] As R¹⁰,

[0585] (a) the lower alkyl group may be methyl group, ethyl group,isopropyl group, tert-butyl group, or trifluoromethyl group, with methylgroup and trifluoromethyl group being preferred; and

[0586] (b) the lower alkoxy group may be methoxy group, ethoxy group,isopropoxy group, tert-butoxy group, or trifluoromethoxy group, withmethoxy group and trifluoromethoxy group being preferred.

[0587] Among the above, examples of a preferred embodiment of R⁹include:

[0588] (b) a lower alkyl group,

[0589] (c) a lower alkoxy group, and

[0590] forming a ring selected from (a) a tetralin ring optionallysubstituted with R⁸, (b) a naphthalene ring optionally substituted withR⁸ or (c) a 1,3-benzodioxole ring optionally substituted with R⁸,wherein the ring is formed by each pair of R⁹ and R¹⁰ together with thebenzene ring to which they are attached. More preferred embodiment of R⁹may be the forming of a ring selected from (a) a tetralin ringoptionally substituted with R⁸, (b) a naphthalene ring optionallysubstituted with R⁸ and (c) a 1,3-benzodioxole ring optionallysubstituted with R⁸, wherein the ring is formed by each pair of R⁹ andR¹⁰ together with the benzene ring to which they are attached. Further,the forming of a naphthalene ring optionally substituted with R⁸ may bementioned as a more preferred embodiment of R⁹.

[0591] Among the above, examples of a preferred embodiment of R¹⁰include

[0592] (a) a lower alkyl group,

[0593] (b) a lower alkoxy group, and

[0594] forming a ring selected from (a) a tetralin ring optionallysubstituted with R⁸, (b) a naphthalene ring optionally substituted withR⁸ and (c) a 1,3-benzodioxole ring optionally substituted with R⁸,wherein the ring is formed by each pair of R⁹ and R¹⁰ together with thebenzene ring to which they are attached. More preferred embodiment ofR¹⁰ may be the forming of a ring selected from (a) a tetralin ringoptionally substituted with R⁸, (b) a naphthalene ring optionallysubstituted with R⁸ and (c) a 1,3-benzodioxole ring optionallysubstituted with R⁸, wherein the ring is formed by each pair of R⁹ andR¹⁰ together with the benzene ring to which they are attached. Further,the forming of a naphthalene ring optionally substituted with R⁸ may bementioned as a more preferred embodiment of R¹⁰.

[0595] The dashed line linking one R¹⁰ to the other R¹⁰ means that oneR¹⁰ may be bonded to the other R¹⁰ via an oxygen atom. It is preferred,however, that two R¹⁰ are not bonded to each other.

[0596] Ar¹ and Ar² independently represent a phenyl group substitutedwith from zero to five substituents selected from straight-chain orbranched-chain lower alkyl group, halogen or lower alkoxy group. As thesaid substituents

[0597] (a) the straight or branched chain lower alkyl group may bemethyl group, ethyl group, isopropyl group, or tert-butyl group, withmethyl group being preferred;

[0598] (b) the halogen substituent may be fluorine, chlorine, bromine,or iodine, with fluorine being preferred; and

[0599] (c) the lower alkoxy group may be methoxy group, ethoxy group,isopropoxy group, or tert-butoxy group, with methoxy group beingpreferred.

[0600] Ar¹ and Ar² may be the same or different and are preferably aphenyl group substituted with from zero to five substituents set forthabove. Further, Ar¹ and Ar² may be the same or different and are alsopreferably a phenyl group substituted with from two to five substituentsset forth above in which at least two substituents are straight orbranched chain lower alkyl groups. Further, it may be particularlypreferred that Ar¹ and Ar² are the same and are a phenyl groupsubstituted with from two to five substituents set forth above in whichat least two substituents are straight or branched chain lower alkylgroups.

[0601] Specific examples of Ar¹ and Ar² include phenyl group, m-tolylgroup, p-fluorophenyl group, p-chlorophenyl group, 3,5-dimethyl-phenylgroup (xylyl group), 3,5-di-tert-butylphenyl group, p-methoxyphenylgroup, p-tert-butylphenyl group, p-tolyl group, and3,5-dimethyl-4-methoxyphenyl group. Preferably, Ar¹ and Ar² eachindependently may be 3,5-dimethylphenyl group (xylyl group) or3,5-dimethyl-4-methoxyphenyl group. Further, it may be particularlypreferred that Ar¹ and Ar² are the same and represent 3,5-dimethylphenylgroup (xylyl group) or 3,5-dimethyl-4-methoxy-phenyl group.

[0602] Further, among the optically active bidentate phosphine ligandsrepresented by the general formula (13), the following class ofcompounds may be preferred. That is, the optically active bidentatephosphine ligands of the formula (13) in which R⁸ represents hydrogen,methyl group, or trifluoromethyl group; R⁹ represents hydrogen, methylgroup, trifluoromethyl group, methoxy group, or trifluoromethoxy group,or alternatively R⁹ is bonded to R¹⁰ to form a tetralin ring or anaphthalene ring; R¹⁰ represents methyl group, trifluoromethyl group,methoxy group, or trifluoromethoxy group, or alternatively R¹⁰ is bondedto R⁹ to form a tetralin ring or a naphthalene ring; one R¹⁰ and theother R¹⁰ are not bonded to each other via an oxygen atom; Ar¹ and Ar²are the same and represent phenyl group, m-tolyl group, p-fluorophenylgroup, p-chlorophenyl group, 3,5-dimethylphenyl group (xylyl group),3,5-di-tert-butylphenyl group, p-methoxyphenyl group, p-tert-butylphenylgroup, p-tolyl group, or 3,5-dimethyl-4-methoxyphenyl group.

[0603] Preferred examples of the optically active bidentate phosphineligand having the above substituents are mentioned below. That is, suchpreferred examples include each optical isomer of2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl (abbreviated name: BINAP);BINAP derivatives in which the naphthalene ring of BINAP is partiallyreduced, such as each optical isomer of2,2′-bis(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl(abbreviated name: H₈BINAP); BINAP derivatives in which the naphthalenering of BINAP carries substituent(s), such as each optical isomer of2,2′-bis-(diphenylphosphino)-6,6′-dimethyl-1,1′-binaphthyl (abbreviatedname: 6MeBINAP); BINAP derivatives in which the benzene ring on thephosphorus atom of BINAP is substituted with lower alkyl group(s), suchas each optical isomer of 2,2′-bis-(di-p-tolylphosphino)-1,1′-binaphthyl(abbreviated name: Tol-BINAP), each optical isomer of2,2′-bis[bis(3-methylphenyl)phosphino]-1,1′-binaphthyl, each opticalisomer of2,2′-bis[bis(3,5-di-tert-butylphenyl)phosphino]-1,1′-binaphthyl, eachoptical isomer of2,2′-bis[bis(4-tert-butylphenyl)phosphino]-1,1′-binaphthyl, each opticalisomer of 2,2′-bis[bis(3,5-dimethylphenyl)phosphino]-1,1′-binaphthyl(abbreviated name: Xyl-BINAP), and each optical isomer of2,2′-bis[bis(3,5-dimethyl-4-methoxyphenyl)phosphino]-1,1′-binaphthyl(abbreviated name: Dmanyl-BINAP); BINAP derivatives in which thenaphthalene ring of BINAP carries substituent(s) and the benzene ring onthe phosphorus atom of BINAP is substituted with from 1 to 5 lower alkylsubstituents, such as each optical isomer of2,2′-bis[bis-(3,5-dimethylphenyl)phosphino]-6,6′-dimethyl-1,1′-binaphthyl(abbreviated name: Xyl-6MeBINAP); and, BINAP derivatives in which thenaphthalene ring of BINAP is condensed with a saturated hydrocarbonring, such as each optical isomer of3,3′-bis-(diphenylphosphanyl)-13,13′-dimethyl-12,13,14,15,16,17,12′,13′,14′,15′,16′,17′-dodecahydro-11H,11′H-[4,4′]bi[cyclopenta[a]phenanthrenyl].Further, particularly preferred examples include each optical isomer of2,2′-bis[bis-(3,5-dimethylphenyl)phosphino]-1,1′-binaphthyl (abbreviatedname: Xyl-BINAP); each optical isomer of2,2′-bis[bis(3,5-dimethyl-4-methoxyphenyl)phosphino]-1,1′-binaphthyl(abbreviated name: Dmanyl-BINAP); and BINAP derivatives in which thenaphthalene ring of BINAP carries substituent(s) and the benzene ring onthe phosphorus atom of BINAP is substituted with from 1 to 5 lower alkylsubstituents, such as each optical isomer of2,2′-bis[bis-(3,5-dimethylphenyl)phosphino]-6,6′-dimethyl-1,1′-binaphthyl(abbreviated name: Xyl-6MeBINAP).

[0604] Further, each optical isomer of2,2′-bis[bis(4-fluorophenyl)phosphino]-1,1′-binaphthyl, and each opticalisomer of 2,2′-bis-[bis(4-chlorophenyl)phosphino]-1,1′-binaphthyl may bealso mentioned as examples of BINAP derivatives carrying fluorinesubstituent(s) and/or chlorine substituent(s).

[0605] In addition, bidentate tertiary phosphine compounds other thanthe BINAP derivatives, such as each optical isomer of2,2′-bis(diphenylphosphino)-6,6′-disubstituted-1,1′-biphenylderivatives, may also be preferred. Specific examples thereof may bebiphenyl derivatives including each optical isomer of6,6′-bis(diphenylphosphino)-3,3′-dimethoxy-2,2′,4,4′-tetramethyl-1,1′-biphenyl,each optical isomer of6,6′-bis[bis(4-methoxyphenyl)phosphanyl]-3,3′-dimethoxy-2,4,2′,4′-tetramethylbiphenyl,each optical isomer of2,2′-bis(diphenylphosphino)-6,6′-dimethylbiphenyl, each optical isomerof 2,2′-bis(diphenylphosphanyl)-4,6,4′,6′-tetramethylbiphenyl, eachoptical isomer of[4,4′-bis(dimethylamino)-6,6′-dimethylbiphenyl-2,2′-diyl]bis(diphenylphosphine),each optical isomer of5,7-dihydrodibenzo[c,e]oxepin-1,11-bis(diphenylphosphine), and eachoptical isomer of[(5,6),(5′,6′)-bis(methylenedioxy)biphenyl-2,2′-diyl]bis(diphenylphosphine)(abbreviated name: SEGPHOS). Of course, optically active bidentatephosphine ligands which can be used according to the present inventionshould not be limited to the above.

[0606] These optically active BINAP derivatives may be preparedaccording to the process using a nickel catalyst described in theliterature (Dongwei Cai, et al., J. Org. Chem., 59, pp. 7180-7181(1994); or Scott A. Laneman, et al., Chem. Commun., pp. 2359-2360(1997)), or the process comprising reducing BINAPO derivatives (obtainedby oxidizing trivalent phosphorus atom of BINAP derivatives topentavalent phosphorus atom) with trichlorosilane described in theliterature (Hidemasa Takaya; Susumu Akutagawa; Ryoji Noyori, et al., J.Org. Chem., 51, pp. 629-635 (1986)), or the process described inJP-B-07-68260. Further, the above optically active biphenyl derivativesmay be prepared by the process for preparing the BINAP derivatives setforth above. Further, optically active biphenyl derivatives in which thebenzene ring of the biphenyl carries alkoxy substituent(s) may beprepared according to the process described in JP-A-11-269185.

[0607] On the other hand, the diamine ligand is represented by thegeneral formula (14):

[0608] wherein m represents an integer of from 0 to 2,

[0609] R¹¹ represents:

[0610] (a) hydrogen,

[0611] (b) a straight-chain lower alkyl group,

[0612] (c) a branched-chain lower alkyl group,

[0613] (d) a cyclic lower alkyl group,

[0614] (e) a phenyl group substituted with from zero to five lower alkylor lower alkoxy groups,

[0615] (f) a 1-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups, or

[0616] (g) a 2-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups;

[0617] provided that (I) when R¹¹ is hydrogen, then R¹² and R¹³ areindependently represent:

[0618] (a) hydrogen,

[0619] (b) a straight-chain lower alkyl group,

[0620] (c) a branched-chain lower alkyl group,

[0621] (d) a cyclic lower alkyl group,

[0622] (e) a phenyl group substituted with from zero to five lower alkylor lower alkoxy groups,

[0623] (f) a 1-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups, or

[0624] (g) a 2-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups, or

[0625] (h) alternatively, R¹² and R¹³ may be bonded to each other toform a ring selected from:

[0626] (h-i) a cycloalkyl ring, or

[0627] (h-2) a heteroatom-containing heterocyclic ring; or

[0628] (II) when R¹¹ is other than hydrogen, then R¹² represents:

[0629] (a) a straight-chain lower alkyl group,

[0630] (b) a branched-chain lower alkyl group,

[0631] (c) a cyclic lower alkyl group,

[0632] (d) a phenyl group substituted with from zero to five lower alkylor lower alkoxy groups,

[0633] (e) a 1-naphthyl group substituted with from zero to seven-loweralkyl or lower alkoxy groups, or

[0634] (f) a 2-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups; and

[0635] R¹³ represents:

[0636] (a) hydrogen,

[0637] (b) a lower alkyl group, or

[0638] (c) a benzyl group.

[0639] In the general formula (14), m represents an integer of from 0 to2, with 0 being preferred.

[0640] R¹¹ represents

[0641] (a) hydrogen,

[0642] (b) a straight-chain lower alkyl group,

[0643] (c) a branched-chain lower alkyl group,

[0644] (d) a cyclic lower alkyl group,

[0645] (e) a phenyl group substituted with from zero to five lower alkylor lower alkoxy groups,

[0646] (f) a 1-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups, or

[0647] (g) a 2-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy group.

[0648] Examples of the group represented by R¹¹ are as follows.

[0649] Examples of

[0650] (b) a straight-chain lower alkyl group,

[0651] (c) a branched-chain lower alkyl group, or

[0652] (d) a cyclic lower alkyl group

[0653] include, but are not limited to, methyl group, ethyl group,n-propyl group, isopropyl group, n-butyl group, sec-butyl group,isobutyl group, tert-butyl group, cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, and cycloheptyl group, withcyclobutyl group, cyclopentyl group and cyclohexyl group beingpreferred.

[0654] Examples of (e) a phenyl group substituted with from zero to fivelower alkyl or lower alkoxy groups include, but are not limited to,phenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group,2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenylgroup, 3,5-dimethylphenyl group, 2,3,4-trimethylphenyl group,2,3,5-trimethylphenyl group, 2,3,6-trimethylphenyl group,2,4,5-trimethylphenyl group, 2,4,6-trimethylphenyl group,3,4,5-trimethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenylgroup, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group,2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group,2,6-dimethoxyphenyl group, 3,4-dimethoxyphenyl group,3,5-dimethoxyphenyl group, 2,3,4-trimethoxyphenyl group,2,3,5-trimethoxyphenyl group, 2,3,6-trimethoxyphenyl group,2,4,5-trimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, and3,4,5-trimethoxyphenyl group. Preferred examples thereof include3,4-dimethylphenyl group, 3,5-dimethylphenyl group,3,4,5-trimethylphenyl group, 3-methoxyphenyl group, 4-methoxyphenylgroup, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, and3,4,5-trimethoxyphenyl group, with 3,5-dimethylphenyl group,4-methoxyphenyl group, 3,4-dimethoxyphenyl group, and3,5-dimethoxyphenyl group being more preferred.

[0655] Preferred examples of (f) a 1-naphthyl group substituted withfrom zero to seven lower alkyl or lower alkoxy groups include, but arenot limited to, 4-methoxy-1-naphthyl group.

[0656] Preferred examples of (g) a 2-naphthyl group substituted withfrom zero to seven lower alkyl or lower alkoxy groups include, but arenot limited to, 1-methoxy-2-naphthyl group and 4-methoxy-2-naphthylgroup.

[0657] Among the above, R¹¹ is preferably

[0658] (a) hydrogen, or

[0659] (e) a phenyl group substituted with from zero to five lower alkylor lower alkoxy groups; and

[0660] particularly preferably

[0661] (e) a phenyl group substituted with from zero to five lower alkylor lower alkoxy groups.

[0662] (I) When R¹¹ is (a) hydrogen, then R¹² and R¹³ are independentlyrepresent:

[0663] (Ia) hydrogen,

[0664] (Ib) a straight-chain lower alkyl group,

[0665] (Ic) a branched-chain lower alkyl group,

[0666] (Id) a cyclic lower alkyl group,

[0667] (Ie) a phenyl group substituted with from zero to five loweralkyl or lower alkoxy groups,

[0668] (If) a 1-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups, or

[0669] (Ig) a 2-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups, or

[0670] (Ih) alternatively, R¹² and R¹³may be bonded to each other toform a ring selected from:

[0671] (h-i) a cycloalkyl ring, or

[0672] (h-2) a heteroatom-containing heterocyclic ring; or,alternatively,

[0673] (II) when R¹¹ is other than hydrogen, then R¹² represents:

[0674] (IIa) a straight-chain lower alkyl group,

[0675] (IIb) a branched-chain lower alkyl group,

[0676] (IIc) a cyclic lower alkyl group,

[0677] (IId) a phenyl group substituted with from zero to five loweralkyl or lower alkoxy groups,

[0678] (IIe) a 1-naphthyl group substituted with from zero to sevenlower alkyl or lower alkoxy groups, or

[0679] (IIf) a 2-naphthyl group substituted with from zero to sevenlower alkyl or lower alkoxy groups; and

[0680] R¹³ represents:

[0681] (IIg) hydrogen,

[0682] (IIh) a lower alkyl group, or

[0683] (IIi) a benzyl group.

[0684] (I) When R¹¹ is (a) hydrogen, examples of the groups representedby R¹² and R¹³ are each independently as follows.

[0685] Examples of

[0686] (Ib) a straight-chain lower alkyl group,

[0687] (Ic) a branched-chain lower alkyl group, or

[0688] (Id) a cyclic lower alkyl group,

[0689] include, but are not limited to, methyl group, ethyl group,n-propyl group, isopropyl group, n-butyl group, sec-butyl group,isobutyl group, tert-butyl group, cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, and cycloheptyl group, withcyclobutyl group, cyclopentyl group, and cyclohexyl group beingpreferred.

[0690] Examples of (Ie) a phenyl group substituted with from zero tofive lower alkyl or lower alkoxy groups include, but are not limited to,phenyl group, 2,3-dimethylphenyl group, 2,4-dimethyl-phenyl group,2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenylgroup, 3,5-dimethylphenyl group, 2,3,4-trimethylphenyl group,2,3,5-trimethylphenyl group, 2,3,6-trimethylphenyl group,2,4,5-trimethylphenyl group, 2,4,6-trimethylphenyl group,3,4,5-trimethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenylgroup, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group,2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group,2,6-dimethoxyphenyl group, 3,4-dimethoxyphenyl group,3,5-dimethoxyphenyl group, 2,3,4-trimethoxyphenyl group,2,3,5-trimethoxyphenyl group, 2,3,6-trimethoxyphenyl group,2,4,5--trimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, and3,4,5-trimethoxyphenyl group. Preferred examples thereof include phenylgroup, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group,3,4,5-trimethylphenyl group, 3-methoxyphenyl group, 4-methoxyphenylgroup, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, and3,4,5-trimethoxyphenyl group, with phenyl group, 3,5-dimethylphenylgroup, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group, and3,5-dimethoxyphenyl group being more preferred.

[0691] Preferred examples of (If) a 1-naphthyl group substituted withfrom zero to seven lower alkyl or lower alkoxy groups include, but arenot limited to, 1-naphthyl group and 4-methoxy-1-naphthyl group.

[0692] Preferred examples of (Ig) a 2-naphthyl group substituted withfrom zero to seven lower alkyl or lower alkoxy groups include, but arenot limited to, 2-naphthyl group, 1-methoxy-2-naphthyl group, and4-methoxy-2-naphthyl group.

[0693] Alternatively, (Ih) R² and R³ may be bonded to each other to forma ring, and examples thereof are as follows.

[0694] Examples of (Ih-1) a cycloalkyl ring include, but are not limitedto, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexanering, cycloheptane ring, and cyclooctane ring, with cyclohexane ringbeing preferred;

[0695] Examples of (Ih-2) a heteroatom-containing heterocyclic ringinclude, but are not limited to, tetrahydrofuran ring, tetrahydropyranring, and dioxane ring.

[0696] Among the above, R¹² and R¹³ may be preferably:

[0697] (Ie) a phenyl group substituted with from zero to five loweralkyl or lower alkoxy groups,

[0698] (If) a 1-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups, or

[0699] (Ig) a 2-naphthyl group substituted with from zero to seven loweralkyl or lower alkoxy groups, or

[0700] (Ih) alternatively R¹² and R¹³ may be preferably bonded to eachother to form (Ih-1) a cycloalkyl ring.

[0701] R¹² and R¹³ may be particularly preferably:

[0702] (Ie) a phenyl group substituted with from zero to five loweralkyl or lower alkoxy group, or

[0703] (Ih) alternatively R¹² and R¹³ may be particularly preferablybonded to each other to form (Ih-1) a cycloalkyl ring.

[0704] However, R¹² and R¹³ are not limited to the above.

[0705] Further, (II) when R¹¹ is other than hydrogen, examples of thegroups represented by R¹² are as follows.

[0706] Examples of

[0707] (IIa) a straight-chain lower alkyl group,

[0708] (IIb) a branched-chain lower alkyl group, or

[0709] (IIc) a cyclic lower alkyl group,

[0710] include, but are not limited to, methyl group, ethyl group,n-propyl group, isopropyl group, n-butyl group, sec-butyl group,isobutyl group, tert-butyl group, cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, and cycloheptyl group, withcyclobutyl group, cyclopentyl group, and cyclohexyl group beingpreferred.

[0711] Examples of (IId) a phenyl group substituted with from zero tofive lower alkyl or lower alkoxy groups include, but are not limited to,phenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group,2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenylgroup, 3,5-dimethylphenyl group, 2,3,4-trimethylphenyl group,2,3,5-trimethylphenyl group, 2,3,6-trimethylphenyl group,2,4,5-trimethylphenyl group, 2,4,6-trimethylphenyl group,3,4,5-trimethylphenyl group, 2-methoxy-phenyl group, 3-methoxyphenylgroup, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group,2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group,2,6-dimethoxyphenyl group, 3,4-dimethoxyphenyl group,3,5-dimethoxy-phenyl group, 2,3,4-trimethoxyphenyl group,2,3,5-trimethoxyphenyl group, 2,3,6-trimethoxyphenyl group,2,4,5-trimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, and3,4,5-trimethoxyphenyl group. Preferred examples thereof include phenylgroup, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group,3,4,5-trimethylphenyl group, 3-methoxyphenyl group, 4-methoxyphenylgroup, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, and3,4,5-trimethoxyphenyl group, with phenyl group, 3,5-dimethylphenylgroup, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group, and3,5-dimethoxyphenyl group being more preferred.

[0712] Preferred examples of (IIe) a 1-naphthyl group substituted withfrom zero to seven lower alkyl or lower alkoxy groups include, but arenot limited to, 1-naphthyl group and 4-methoxy-1-naphthyl group.

[0713] Preferred examples of (IIf) a 2-naphthyl group substituted withfrom zero to seven lower alkyl or lower alkoxy groups include, but arenot limited to, 2-naphthyl group, 1-methoxy-2-naphthyl group and4-methoxy-2-naphthyl group.

[0714] Then, examples of the groups represented by R¹³ are as follows.

[0715] Examples of (IIh) a lower alkyl group include, but are notlimited to, methyl group, ethyl group, isopropyl group, and isobutylgroup. Preferred examples include methyl group and isopropyl group, withmethyl group being particularly preferred.

[0716] (II) When R¹¹ is other than hydrogen, R¹² may be preferably

[0717] (IId) a phenyl group substituted with from zero to five loweralkyl or lower alkoxy groups,

[0718] (IIe) a 1-naphthyl group substituted with from zero to sevenlower alkyl or lower alkoxy groups, or

[0719] (IIf) a 2-naphthyl group substituted with from zero to sevenlower alkyl or lower alkoxy groups; and

[0720] particularly preferably

[0721] (IId) a phenyl group substituted with from zero to five loweralkyl or lower alkoxy groups;

[0722] more preferably, R¹² may be the same with R¹¹. However, R¹² isnot limited to the above.

[0723] Then, R¹³ may be preferably

[0724] (IIh) a lower alkyl group, or

[0725] (IIi) a benzyl group;

[0726] more preferably

[0727] (IIh) a lower alkyl group.

[0728] However, R¹³ is not limited to the above.

[0729] Among the diamine ligands represented by the general formula(14), the following class of compounds may be preferred. That is, thediamine ligands of the formula (14) in which m is 0; R¹¹ represents3,5-dimethylphenyl group, 4-methoxyphenyl group, 3,4-dimethoxyphenylgroup, or 3,5-dimethoxyphenyl group; R¹² is the same with R¹¹ andrepresents 3,5-dimethylphenyl group, 4-methoxyphenyl group,3,4-dimethoxyphenyl group, or 3,5-dimethoxyphenyl group; and R¹³represents methyl group, isopropyl group or benzyl group.

[0730] Examples of the diamine ligand are mentioned below. That is, suchexamples include methylenediamine, ethylenediamine, 1,2-diaminopropane,1,3-diaminopropane, 1,4-diaminobutane, 2,3-diaminobutane,1,2-cyclopentanediamine, 1,2-cyclohexanediamine,1,1-diphenylethylenediamine, 1,1-di(p-methoxyphenyl)ethylenediamine,1,1-di(3,5-dimethoxyphenyl)ethylenediamine, and1,1-dinaphthylethylenediamine. Optically active diamine compounds may bealso used. Examples thereof include, for example, optically active1,2-diphenylethylenediamine (abbreviated name: DPEN),1,2-di(p-methoxyphenyl)ethylenediamine, 1,2-cyclohexanediamine,1,2-cycloheptanediamine, 2,3-dimethylbutanediamine,1-methyl-2,2-diphenylethylenediamine,1-isobutyl-2,2-diphenylethylenediamine,1-isopropyl-2,2-diphenylethylenediamine,1-benzyl-2,2-diphenylethylenediamine,

[0731] 1-methyl-2,2-di(p-methoxyphenyl)ethylenediamine (abbreviatedname: DAMEN), 1-isobutyl-2,2-di(p-methoxyphenyl)-ethylenediamine(abbreviated name: DAIBEN),1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine (abbreviated name:DAIPEN), 1-benzyl-2,2-di(p-methoxyphenyl)ethylenediamine,1-methyl-2,2-di(3,5-dimethoxyphenyl)ethylenediamine,1-isopropyl-2,2-di(3,5-dimethoxyphenyl)ethylenediamine,1-isobutyl-2,2-di(3,5-dimethoxy-phenyl)ethylenediamine,1-benzyl-2,2-di(3,5-dimethoxyphenyl)ethylenediamine,1-methyl-2,2-dinaphthylethylenediamine,1-isobutyl-2,2-dinaphthylethylenediamine,1-isopropyl-2,2-dinaphthylethylenediamine, and1-benzyl-2,2-dinaphthylethylenediamine.

[0732] Further, optically active diamine compounds which can be used arenot limited to the abovementioned optically active ethylenediaminederivatives. Optically active propanediamine, butanediamine andcyclohexanediamine derivatives may be also used.

[0733] In addition, these diamine ligands may be prepared by the processstarting from α-amino acid described in the literature (Burrows, C. J.,et al., Tetrahedron Letters, 34(12), pp. 1905-1908 (1993)), or by avariety of processes described in the general remark (T. Le Gall, C.Mioskowski, and D. Lucet, Angew. Chem. Int. Ed., 37, pp. 2580-2627(1998)).

[0734] Preferred examples of the optically active diamine ligand arementioned below. That is, the preferred examples include1-methyl-2,2-diphenylethylenediamine,1-isobutyl-2,2-diphenylethylenediamine,1-isopropyl-2,2-diphenylethylenediamine,1-benzyl-2,2-diphenylethylenediamine,1-methyl-2,2-di(p-methoxyphenyl)ethylenediamine (abbreviated name:DAMEN), 1-isobutyl-2,2-di(p-methoxyphenyl)ethylenediamine (abbreviatedname: DAIBEN), 1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine(abbreviated name: DAIPEN),1-benzyl-2,2-di(p-methoxyphenyl)ethylenediamine,1-methyl-2,2-di(3,5-dimethoxyphenyl)ethylenediamine,1-isopropyl-2,2-di(3,5-dimethoxyphenyl)ethylenediamine,1-isobutyl-2,2-di(3,5-dimethoxyphenyl)ethylenediamine, and1-benzyl-2,2-di(3,5-dimethoxyphenyl)ethylenediamine.

[0735] Further, more preferred examples of the optically active diamineligand include 1-methyl-2,2-di(p-methox-yphenyl)ethylenediamine(abbreviated name: DAMEN),1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine (abbreviated name:DAIPEN), 1-benzyl-2,2-di(p-methoxyphenyl)ethylenediamine,1-methyl-2,2-di(3,5-dimethoxy-phenyl)ethylenediamine,1-isopropyl-2,2-di(3,5-dimethoxyphenyl)ethylenediamine, and1-benzyl-2,2-di(3,5-dimethoxyphenyl)ethylenediamine.

[0736] The ruthenium/bidentate phosphine/diamine complex to be used bythe present invention may be prepared by the known process described inJP-A-11-189600. More specifically, the complex may be synthesized byreacting the ruthenium compound as a starting material with thebidentate phosphine ligand and the diamine ligand sequentially orinversely or simultaneously. As a ruthenium compound which is a startingmaterial for synthesizing the complex, zerovalent, monovalent, divalent,trivalent or highvalent ruthenium compounds may be used. When azerovalent or monovalent ruthenium compound is used, it is needed tooxidize the ruthenium atom before the final reaction step. When adivalent ruthenium compound is used, the complex may be synthesized byreacting the ruthenium compound with the phosphine ligand and thediamine ligand sequentially or inversely or simultaneously. When atrivalent or polyvalent ruthenium compound is used as a startingmaterial, it is needed to reduce the ruthenium atom before the finalreaction step.

[0737] Examples of a starting ruthenium compound to be used includeinorganic ruthenium compounds, such as ruthenium(III) chloride hydrate,ruthenium(III) bromide hydrate, and ruthenium(III) iodide hydrate;ruthenium compounds coordinated with diene, such as[ruthenium(norbornadiene) dichloride] polymer complex,[ruthenium(cyclooctadiene) dichloride] polymer complex, andbis[(methylallyl)ruthenium(cyclooctadiene)]; ruthenium complex compoundscoordinated with aromatic compound, such as [ruthenium(benzene)dichloride] dimer complex, [ruthenium(p-cymene) dichloride] dimercomplex, [ruthenium(trimethylbenzene) dichloride] dimer complex, and[ruthenium(hexamethylbenzene) dichloride] dimer complex; and rutheniumcomplex compounds coordinated with phosphine, such asdichlorotris(triphenylphosphine)ruthenium. In addition to theabovementioned neutral ruthenium complexes, cationic rutheniumcomplexes, such as [chlororuthenium(binap)(benzene)] chloride, and[chlororuthenium(binap)(p-cymene)] chloride (described in J. Org. Chem.,59, p 3064 (1994)), and anionic complexes may be used. Further,ruthenium compounds to be used are not limited to the compoundsmentioned above as long as they have ligands which can be substitutedfor bidentate phosphine ligand and diamine ligand. As the startingmaterial, a variety of ruthenium compounds described in, for example,COMPREHENSIVE ORGANOMETALLIC CHEMISTRY II, Vol. 7, pp. 294-296(PERGAMON) may be used.

[0738] A preferred example of the process uses a divalent rutheniumcompound as the starting ruthenium compound and comprises reacting theruthenium compound with the bidentate phosphine compound and the diaminecompound sequentially or inversely or simultaneously. For example, aruthenium compound coordinated with diene, such as[ruthenium(norbornadiene) dichloride] polymer complex,[ruthenium(cyclooctadiene) dichloride] polymer complex orbis[(methylallyl)ruthenium(cyclooctadiene)], a ruthenium complexcompound coordinated with aromatic compound, such as [ruthenium(benzene)dichloride] dimer complex, [ruthenium(p-cymene) dichloride] dimercomplex, [ruthenium(trimethylbenzene) dichloride] dimer complex or[ruthenium(hexamethylbenzene) dichloride] dimer complex, or a rutheniumcomplex compound coordinated with phosphine, such asdichlorotris(triphenylphosphine)ruthenium, may be reacted with abidentate phosphine compound in aromatic hydrocarbon solvent (such astoluene or xylene), aliphatic hydrocarbon solvent (such as pentane orhexane), halogen-containing hydrocarbon solvent (such asdichloromethane), ether type solvent (such as diethyl ether ortetrahydrofuran), alcohol type solvent (such as methanol, ethanol,2-propanol, butanol or benzyl alcohol), or heteroatom-containing organicsolvent (such as acetonitrile, N,N-dimethylformamide (DMF),N,N-dimethylacetamide(DMA), N-methylpyrrolidone (NMP), ordimethylsulfoxide (DMSO)) at reaction temperatures ranging from −100° C.to 200° C. to obtain a bidentate phosphine/ruthenium halide complex.More preferably, a bidentate phosphine/ruthenium halide complex may beobtained by the process described in Masato Kitamura; Makoto Tokunaga;Takeshi Ohkuma; and Ryoji Noyori, Organic Synthesis, 71, pp. 1-13(1993), which process comprises heating a commercially availablecompound of [RuCl₂(C₆H₆)]₂ and a bidentate phosphine compound in anamount of from 1.0 to 1.05 mol for 1 mol of the Ru metal in a solventselected from DMF and DMA (the amount of the solvent to be used is from10 to 20 mL per mmol of the bidentate phosphine compound) at 100° C. forfrom 10 to 15 minutes; and distilling off the solvent.

[0739] The thus obtained bidentate phosphine/ruthenium halide complexmay be reacted with a diamine compound in aromatic hydrocarbon solvent(such as toluene or xylene), aliphatic hydrocarbon solvent (such aspentane or hexane), halogen-containing hydrocarbon solvent (such asdichloromethane), ether type solvent (such as diethyl ether ortetrahydrofuran), alcohol type solvent (such as methanol, ethanol,2-propanol, butanol, or benzyl alcohol), or heteroatom-containingorganic solvent (such as acetonitrile, DMF, DMA, NMP, or DMSO) atreaction temperatures ranging from −100° C. to 200° C. to yield adiamine/bidentate phosphine/ruthenium halide complex. The reaction ispreferably carried out in a halogen-containing hydrocarbon solvent suchas dichloromethane at temperatures ranging from 10C to 30° C. for from0.5 to 1.5 hours to yield a diamine/bidentate phosphine/ruthenium halidecomplex. Further, under the same reaction conditions, adiamine/bidentate phosphine/ruthenium halide complex may be alsoobtained by reacting a cationic ruthenium complex such as[chlororuthenium-(binap)(benzene)] chloride with a diamine compound.

[0740] Further, according to one of the most preferred characteristicembodiments of the present invention, the process uses adiamine/bidentate phosphine/ruthenium halide complex obtained as setforth above as a catalyst precursor and comprises a step of previouslyactivating the complex precursor by a hydrogenation reaction in thepresence of a base or by a hydride-forming reaction under a hydrogentransfer reducing reaction condition; and then a step of reacting aketone compound containing a nitrogenous or oxygenic functional group.Specifically, a diamine/bidentate phosphine/ruthenium hydride complexmay be obtained by reacting a diamine/bidentate phosphine/rutheniumhalide complex with hydrogen, a metal hydride (such as sodiumborohydride or lithium aluminium hydride), an organometallic compound(such as methylmagnesium bromide, ethylmagnesium bromide,propylmagnesium bromide, methyllithium, ethyllithium, or propyllithium),or an alkali or alkaline earth metal salt (such as KOH, K₂CO₃, KOCH₃,KOCH(CH₃)₂, KC₁₀H₈, tert-BuOK, NaOH, Na₂CO₃, NaOCH₃, NaOCH(CH₃)₂, LiOH,LiOCH₃, or LiOCH(CH₃)₂) in aromatic hydrocarbon solvent (such as tolueneor xylene), aliphatic hydrocarbon solvent (such as pentane or hexane),halogen-containing hydrocarbon solvent (such as dichloromethane), ethertype solvent (such as diethyl ether or tetrahydrofuran), alcohol typesolvent (such as methanol, ethanol, 2-propanol, butanol, or benzylalcohol), or heteroatom-containing organic solvent (such asacetonitrile, DMF, DMA, NMP, or DMSO), preferably, in 2-propanol, attemperatures ranging from −100° C. to 200° C.

[0741] Most preferably, the process comprises reacting adiamine/bidentate phosphine/ruthenium halide complex in the presence ofa base such as potassium tert-butoxide in an amount of from 2 to 10 molof for 1 mol of the halide complex, in a degassed alcohol type solventsuch as 2-propanol at reaction temperatures ranging from 55° C. to 65°C. for 0.5 hour or more to activate the catalyst; then adding a solutionof a ketone compound having a nitrogenous or oxygenic functional groupin a degassed alcohol solvent such as 2-propanol to the activatedcatalyst, or alternatively adding a solution of the catalyst activespecies to a solution of the ketone compound; then introducing hydrogeninto the reactor until a required pressure is obtained; and vigorouslystirring the reaction liquid to yield a diamine/bidentatephosphine/ruthenium hydride complex and, at the same time, to allowasymmetric hydrogenation of the ketone compound to directly proceed.

[0742] Further, a diamine/bidentate phosphine/ruthenium hydride complexmay be also obtained by first converting a bidentate phosphine/rutheniumhalide complex into the corresponding bidentate phosphine/rutheniumhydride complex, followed by a reaction with a diamine compound. Forexample, RuH₂(tolbinap) (dpen) may be obtained by convertingRuCl₂(tolbinap) (dmf)_(n) into RuH₂(tolbinap) (dmf)_(n) (wherein dmfrepresents dimethylformamide), followed by a reaction with DPEN.Further, a bidentate phosphine/ruthenium hydride complex may be obtainedby reacting a bidentate phosphine/ruthenium halide complex withhydrogen, a metal hydride (such as sodium borohydride or lithiumaluminium hydride), an organometallic compound (such as methylmagnesiumbromide, ethylmagnesium bromide, propylmagnesium bromide, methyllithium,ethyllithium, or propyllithium), or an alkali or alkaline earth metalsalt (such as KOH, K₂CO₃, KOCH₃, KOCH(CH₃)₂, KC₁₀H₈, tert-BuOK, NaOH,Na₂CO₃, NaOCH₃, NaOCH(CH₃)₂, LiOH, LiOCH₃, or LiOCH(CH₃)₂) in aromatichydrocarbon solvent (such as toluene or xylene), aliphatic hydrocarbonsolvent (such as pentane or hexane), halogen-containing hydrocarbonsolvent (such as dichloromethane), ether type solvent (such as diethylether or tetrahydrofuran), alcohol type solvent (such as methanol,ethanol, 2-propanol, butanol, or benzyl alcohol), orheteroatom-containing organic solvent (such as acetonitrile, DMF, DMA,NMP, or DMSO) at temperatures ranging from −100° C. to 200° C.

[0743] The thus obtained bidentate phosphine/ruthenium hydride complexcan be converted into the corresponding diamine/bidentatephosphine/ruthenium hydride complex by a reaction with a diaminecompound which may be carried out in aromatic hydrocarbon solvent (suchas toluene or xylene), aliphatic hydrocarbon solvent (such as pentane orhexane), halogen-containing hydrocarbon solvent (such asdichloromethane), ether type solvent (such as diethyl ether ortetrahydrofuran), alcohol type solvent (such as methanol, ethanol,2-propanol, butanol, or benzyl alcohol), or heteroatom-containingorganic solvent (such as acetonitrile, DMF, DMA, NMP, or DMSO) attemperatures ranging from −100° C. to 200° C.

[0744] Examples of ruthenium/bidentate phosphine/diamine complex whichmay be synthesized as set forth above, includetrans-RuCl₂[(S)-xylbinap][(S)-damen], trans-RuCl₂[(R)-xylbinap][(R)-damen], trans-RuCl₂[(S)-xylbinap][(R)-damen],trans-RuCl₂[(R)-xylbinap][(S)-damen],trans-RuCl₂[(S)-xylbinap][(S)-daipen],trans-RuCl₂[(R)-xylbinap][(R)-daipen],trans-RuCl₂[(S)-xylbinap][(R)-daipen],trans-RuCl₂[(R)-xylbinap][(S)-daipen],trans-RuCl₂[(S)-tolbinap][(S)-daipen],trans-RuCl₂[(R)-tolbinap][(R)-daipen],trans-RuCl₂[(R)-tolbinap][(S)-daipen],trans-RuCl₂[(S)-tolbinap]-[(R)-daipen],trans-RuCl₂[(S)-xylbinap][(S,S)-dpen],trans-RuCl₂-[(R)-xylbinap][(R,R)-dpen],trans-RuCl₂[(S)-xylbinap][(R,R)-dpen],trans-RuCl₂[(R)-xylbinap][(S,S)-dpen],trans-RuCl₂[(S)-dmanylbinap][(S)-damen],trans-RuCl₂[(R)-dmanylbinap][(R)-damen],trans-RuCl₂[(S)-dmanylbinap][(R)-damen],trans-RuCl₂[(R)-dmanylbinap][(S)-damen],trans-RuCl₂[(S)-6mebinap][(S)-damen],trans-RuCl₂[(R)-6mebinap][(R)-damen],trans-RuCl₂[(S)-6mebinap]-[(R)-damen],trans-RuCl₂[(R)-6mebinap][(S)-damen],trans-RuCl₂[(S)-xyl-6mebinap][(S)-damen],trans-RuCl₂[(R)-xyl-6mebinap][(R)-damen],trans-RuCl₂[(S)-xyl-6mebinap][(R)-damen], andtrans-RuCl₂[(R)-xyl-6mebinap][(S)-damen].

[0745] In addition, preferred examples of ruthenium/bidentate phosphine/diamine complex, include trans-RuCl₂[(S)-xylbinap][(S)-damen],trans-RuCl₂[(R)-xylbinap][(R)-damen],trans-RuCl₂[(S)-xylbinap][(R)-damen],trans-RuCl₂[(R)-xylbinapl[(S)-damen],trans-RuCl₂[(S)-xylbinap][(S)-daipen],trans-RuCl₂[(R)-xylbinap][(R)-daipen],trans-RuCl₂[(S)-xylbinap][(R)-daipen],trans-RuCl_(2[)(R)-xylbinap][(S)-daipen],trans-RuCl₂[(S)-dmanylbinap][(S)-damen],trans-RuCl₂[(R)-dmanylbinap][(R)-damen],trans-RuCl₂[(S)-dmanylbinap][(R)-damen],trans-RuCl₂[(R)-dmanylbinap][(S)-damen],trans-RuCl₂[(S)-xyl-6mebinap][(S)-damen],trans-RuCl₂[(R)-xyl-6mebinap][(R)-damen],trans-RuCl₂[(S)-xyl-6mebinap][(R)-damen], andtrans-RuCl₂[(R)-xyl-6mebinap][(S)-damen].

[0746] Further, in order to achieve a higher asymmetric yield of thereaction using the ruthenium/bidentate phosphine/diamine complex as ahydrogenation catalyst, it is preferred that the symbols of absoluteconfigurations of an optically active bidentate phosphine ligand and anoptically active diamine ligand are the same [for example, (R,R),[R,(R,R)], or the like]. However, a diamine ligand to be used does notnecessarily contain any asymmetric center.

[0747] Among ketone compounds represented by the general formula (1),the following class of compounds may be mentioned as importantintermediates for synthesizing medicaments which are described in WO97/25311 and WO 99/01431 as being very useful for treating andpreventing diabetes, obesity, hyperlipidemia and the like. That is,aminoketone compounds of the formula (1) wherein n is 0 and A isCH₂NR²R³; and wherein R¹ represents 3-aminophenyl group, 3-nitrophenylgroup, 3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-chloro-3-aminophenyl group,4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-chloro-3-nitrophenyl group, 4-bromo-3-aminophenyl group,4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl group,4-bromo-3-nitrophenyl group, 4-benzyloxy-3-nitrophenyl group,4-benzyloxy-3-aminophenyl group,4-benzyloxy-3-[(benzyl)-(methylsulfonyl)amino]phenyl group,4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl group, or4-benzyloxy-3-[(hydroxy)methyl]phenyl group, preferably substitutedphenyl group such as 4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenylgroup, 4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl group,3-[(benzyl)(methylsulfonyl)amino]phenyl group or4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl group; R² is anamino-protecting group which can be removed under a mild condition andspecifically represents an acyl group, such as acetyl group, propionylgroup, butyryl group, pentanoyl group, hexanoyl group, trifluoroacetylgroup, pivaloyl group, benzoyl group, 4-methoxybenzoyl group,2,4,6-trimethylbenzoyl group or naphthoyl group, a carbamate typeprotecting group, such as tert-butoxycarbonyl group, benzyloxycarbonylgroup, p-methoxybenzyloxycarbonyl group or 2,2,2-trichloroethoxycarbonylgroup, or an aralkyl group such as benzyl group, p-methoxybenzyl groupor p-nitrobenzyl group, preferably benzoyl group or benzyl group; and R³is an ethyl group-which is bonded at its end to the tricyclic fused ringgroup via an oxygen atom and specifically represents2-(dibenzofuran-3-yloxy)ethyl group, 2-(dibenzothiophen-3-yloxy)ethylgroup, 2-(9H-carbazol-2-yloxy)ethyl group,2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl group,2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl group or2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl group, preferably2-(9H-carbazol-2-yloxy)ethyl group. With respect to the abovementionedaminoketone compounds, the following ruthenium/bidentatephosphine/diamine complexes are preferably used as a hydrogenationcatalyst. Examples of such a hydrogenation catalyst includetrans-RuCl₂[(S)-xylbinap][(S)-damen],trans-RuCl₂[(R)-xylbinap][(R)-damen],trans-RuCl₂[(S)-xylbinap][(R)-damen],trans-RuCl₂[(R)-xylbinap][(S)-damen],trans-RuCl₂[(S)-xylbinap][(S)-daipen],trans-RuCl₂[(R)-xylbinap][(R)-daipen],trans-RuCl₂[(S)-xylbinap][(R)-daipen],trans-RuCl₂[(R)-xylbinap][(S)-daipen],trans-RuCl₂[(S)-dmanylbinap][(S)-damen],trans-RuCl₂[(R)-dmanylbinap][(R)-damen],trans-RuCl₂[(S)-dmanylbinap][(R)-damen],trans-RuCl₂[(R)-dmanylbinap][(S)-damen],trans-RuCl₂[(S)-xyl-6mebinap][(S)-damen],trans-RuCl₂[(R)-xyl-6mebinap][(R)-damen],trans-RuCl₂[(S)-xyl-6mebinap][(R)-damen], and trans-RuCl₂[(R)-xyl-6mebinap][(S)-damen].

[0748] Particularly preferred aminoketone compounds which may behydrogenated with the abovementioned ruthenium/bidentatephosphine/diamine complexes as a hydrogenation catalyst may be those inwhich R² is benzyl group. Example thereof include:

[0749]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0750]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0751]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0752]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0753]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0754]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0755]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0756]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0757]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0758]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0759]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0760]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0761]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0762]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0763]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0764]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0765]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0766]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0767]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0768]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0769]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0770]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]-ethanone;

[0771]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0772]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0773]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0774]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0775]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0776]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]-ethanone;

[0777]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]-ethanone;

[0778]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]-ethanone;

[0779]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0780]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0781]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0782]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0783]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0784]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0785]1-(4-chloro-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0786]1-(4-chloro-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzylamino]ethanone;

[0787]1-(4-chloro-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0788]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0789]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0790]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0791]1-(4-bromo-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)-ethyl]benzylamino]ethanone;

[0792]1-(4-bromo-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzylamino]ethanone;

[0793]1-(4-bromo-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0794]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0795]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0796]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0797]1-(3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]-benzylamino]ethanone;

[0798]1-(3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]-benzylamino]ethanone;

[0799]1-(3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]-benzylamino]ethanone;

[0800]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0801]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0802]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0803]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0804]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0805]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanone;

[0806]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0807]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0808]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0809]1-(4-chloro-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzylamino]ethanone;

[0810]1-(4-chloro-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzylamino]ethanone;

[0811]1-(4-chloro-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]-benzylamino]ethanone;

[0812]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0813]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0814]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0815]1-(4-bromo-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yl-oxy)-ethyl]benzylamino]ethanone;

[0816]1-(4-bromo-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzylamino]ethanone;

[0817]1-(4-bromo-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzylamino]ethanone;

[0818]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0819]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;

[0820]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0821]1-(3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]-benzylamino]ethanone;

[0822]1-(3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]-benzylamino]ethanone;

[0823]1-(3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]-benzylamino]ethanone;

[0824]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzylamino]ethanone;

[0825]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzylamino]ethanone;and

[0826]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzylamino]ethanone;

[0827] and their salts with acceptable acids, such as hydrochloride,acetate, hydrobromide and trifluoroacetate.

[0828] Specific examples of the compounds having a benzoyl group as R²include:

[0829]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0830]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0831]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0832]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0833]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0834]1-[4-benzyloxy-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0835]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0836]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0837]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0838]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0839]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0840]1-[4-benzyloxy-3-[(benzyl)(benzylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0841]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0842]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0843]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0844]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0845]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0846]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0847]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0848]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0849]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0850]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]-ethanone;

[0851]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]-ethanone;

[0852]1-[4-bromo-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]-ethanone;

[0853]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0854]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0855]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0856]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]-ethanone;

[0857]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]-ethanone;

[0858]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]-ethanone;

[0859]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0860]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0861]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0862]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0863]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0864]1-(4-benzyloxy-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0865]1-(4-chloro-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0866]1-(4-chloro-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzoylamino]ethanone;

[0867]1-(4-chloro-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0868]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0869]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0870]1-(4-chloro-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0871]1-(4-bromo-3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)-ethyl]benzoylamino]ethanone,

[0872]1-(4-bromo-3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzoylamino]ethanone;

[0873]1-(4-bromo-3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0874]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0875]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0876]1-(4-bromo-3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0877]1-(3-aminophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]-benzoylamino]ethanone;

[0878]1-(3-aminophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]-benzoylamino]ethanone;

[0879]1-(3-aminophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]-benzoylamino]ethanone;

[0880]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0881]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0882]1-(3-aminophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0883]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0884]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0885]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0886]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0887]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0888]1-(4-benzyloxy-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0889]1-(4-chloro-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]benzoylamino]ethanone;

[0890]1-(4-chloro-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]benzoylamino]ethanone;

[0891]1-(4-chloro-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzoylamino]ethanone;

[0892]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0893]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0894]1-(4-chloro-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0895]1-(4-bromo-3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)-ethyl]benzoylamino]ethanone;

[0896]1-(4-bromo-3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)-ethyl]benzoylamino]ethanone;

[0897]1-(4-bromo-3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)-ethyl]benzoylamino]ethanone;

[0898]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0899]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;

[0900]1-(4-bromo-3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone;

[0901]1-(3-nitrophenyl)-2-[[2-(dibenzothiophen-3-yloxy)ethyl]-benzoylamino]ethanone;

[0902]1-(3-nitrophenyl)-2-[[2-(dibenzofuran-3-yloxy)ethyl]-benzoylamino]ethanone;

[0903]1-(3-nitrophenyl)-2-[[2-(9H-carbazol-2-yloxy)ethyl]-benzoylamino]ethanone;

[0904]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzothiophen-6-yloxy)ethyl]benzoylamino]ethanone;

[0905]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydrodibenzofuran-6-yloxy)ethyl]benzoylamino]ethanone;and

[0906]1-(3-nitrophenyl)-2-[[2-(1,2,3,4-tetrahydro-9H-carbazol-7-yloxy)ethyl]benzoylamino]ethanone.

[0907] The amount of a ruthenium/bidentate phosphine/diamine complexrepresented by the general formula (2) to be used as an asymmetrichydrogenation catalyst or an asymmetric hydrogenation catalyst precursorcan vary depending on the type of a reactor used and/or the cost, andmay range from 1/1,000 to 1/3,000,000 mol for 1 mol of the ketonecompound which is a reaction substrate. More preferred practical amountmay range from 1/10,000 to 1/3,000,000 mol for 1 mol of the ketonecompound.

[0908] When X and Y of the ruthenium complex each are hydrogen, theketone compound may be hydrogenated by mixing the ketone compound withthe ruthenium complex without adding a base; and stirring the resultingmixture under a pressurized hydrogen atmosphere. When the ketonecompound is used in a large excess amount with respect to the catalyst,adding a base may be preferred. On the other hand, when X and Y each area group other than hydrogen, the ketone compound may be more effectivelyhydrogenated by previously converting the ruthenium complex into itsactivated hydride form by stirring the ruthenium complex in 2-propanolin the presence of a base such as potassium tert-butoxide at 60° C. for30 minutes; and then mixing the activated hydride form with the ketonecompound followed by pressurizing with hydrogen. The amount of the baseto be added ranges from 0.5 to 100 equivalents, preferably from 2 to 40equivalents for the diamine/bidentate phosphine/ruthenium complex, whenthe substrate, ketone compound is a neutral or basic compound. Further,when the substrate, ketone compound is in the form of a salt with anacidic material such as mineral or organic acid, or has a very weakacidic functional group in the molecule, the base is preferably added ina total amount of a sufficient amount for neutralizing the salt oracidic group and additionally an amount of from 0.5 to 100 equivalents,preferably from 2 to 40 equivalents with respect to thediamine/bidentate phosphine/ruthenium complex. In particular, when anα-aminoketone compound is selected as the reaction substrate, it ispreferably subjected to the process in the form of hydrochloride salt inview of the stability of the substrate per se. Using the base in anamount of from 1.01 to 1.2 mol for 1 mol of the α-aminoketone derivativemonohydrochloride may be mentioned as the most preferred example.

[0909] Examples of the base include alkali metal salts and alkalineearth metal salts, such as KOH, K₂CO₃, KOCH₃, KOCH(CH₃)₂, KOC(CH₃)₃,KC₁OH₈, NaOH, Na₂CO₃, NaOCH₃, NaOCH(CH₃)₂, NaOC(CH₃)₃, LiOH, LiOCH₃,LiOCH(CH₃)₂ and LiO(CH₃)₃, with K₂CO₃, KOCH(CH₃)₂, KOC(CH₃)₃, Na₂CO₃,NaOCH(CH₃)₂ and NaOC(CH₃)₃ being preferred. Any material other than thebase may be used as long as the material can afford thediamine/bidentate phosphine ruthenium hydride form. Examples of thematerial include hydrogen, a metal hydride (such as sodium borohydrideor lithium aluminium hydride) and an organometallic compound (such asmethylmagnesium bromide, ethylmagnesium bromide, propylmagnesiumbromide, methyllithium, ethyllithium or propyllithium).

[0910] Any solvent may be used as long as it can solubilize the rawmaterials of the reaction and the catalyst system. However, the solventis not necessarily required to completely dissolve the raw materials.For example, aromatic hydrocarbon solvent (such as toluene or xylene),aliphatic hydrocarbon solvent (such as pentane or hexane),halogen-containing hydrocarbon solvent (such as dichloromethane), ethertype solvent (such as diethyl ether or tetrahydrofuran), alcohol typesolvent (such as methanol, ethanol, 2-propanol, butanol, ortert-butanol), or heteroatom-containing organic solvent (such asacetonitrile, DMF, DMA, NMP, or DMSO) may be used. Alcohol type solventsmay be preferably used, since the reaction products to be obtained arealcohol compounds. Most preferably, 2-propanol or tert-butanol may beused. When the reaction substrate is difficult to be dissolved in thesolvent, a mixed solvent comprising solvents suitably selected from avariety of solvents mentioned above may be used. Preferred examples ofthe mixed solvent system include 2-propanol/DMF (from 4/1 to 1/4),2-propanol/DMA(from 4/1 to 1/4), tert-butanol/DMF(from 4/1 to 1/4), andtert-butanol/DMA (from 4/1 to 1/4). The amount of the solvent isselected depending on the solubility of the reaction substrate and thecost. For example, when 2-propanol is used, a certain substrate may besubjected to the reaction at from a low concentration of 1% or less to ahigh concentration which is close to a solvent-free reaction condition.The concentration of the substrate ranges preferably from 0.1 to 1.0mol/L. When α-aminoketone compound is used as the substrate, theconcentration thereof is more preferably 0.1 mol/L.

[0911] The present catalyst system has a very high activity. Therefore,the process of the present invention can be carried out under a hydrogenatmosphere at 1 atm. However, the process may be carried out at apressure of from 1 to 200 atm, preferably from 1 to 100 atm. Morepreferably, the process may be carried out at a lower pressure of from 3to 10 atm from the viewpoint of a pressure-proof design of the reactor.However, pressures ranging from 3 to 50 atm are also preferred in viewof the cost of the whole process. Further, when the process is carriedout on a small scale, it can be well carried out at a pressure below 10atm. The process is preferably carried out at temperatures ranging from15° C. to 100° C. in view of the cost. In view of the stability of thecatalyst and substrate, however, the process is more preferably carriedout at temperatures ranging from 15° C. to 80° C., particularly attemperatures ranging from 25° C. to 40° C. close to room temperature.The present process may be characterized by the fact that the processcan proceed at temperatures as low as from −30° C. to 0° C. and alsocharacterized by the fact that the yield and selectivity are hard to beaffected by the reaction temperature. Although the reaction time may bevary depending on the reaction conditions including amount of thecatalyst to be used, concentration of the reaction substrate,temperature and pressure, the reaction can be completed for from severalminutes to several days. For example, the present process may be alsocharacterized by the fact that when the catalyst is used in an amount of1/2,000 mol for 1 mol of the substrate, the reaction can be generallycompleted for from several minutes to 1 hour. These features will bespecifically illustrated in Examples. Further, the ketonecompound-hydrogenating reaction of the present invention may be carriedout by batch system or continuous system.

[0912] The nitrogenous or oxygenic functional group-containing opticallyactive secondary alcohols which can be obtained according to the presentinvention have a high optical purity. Conventional reactions forremoving the protecting groups such as acyl group, benzyl group andketal group and for transforming the functional groups can convert theabovementioned secondary alcohols into the corresponding aminogroup-containing optically active secondary alcohols which may beimportant as a medicament or pesticide per se or as an intermediate forpreparing a medicament or pesticide. The conversion may be carried outby a combined process comprising conventional known reactions set forthbelow.

[0913] That is, when A of the general formula (3) is CH₂NR²R³, asindicated in the reaction scheme (15):

[0914] wherein R¹, n, R² and R³ are as defined above, provided that R²and R³ are not bonded to each other; and * represents an asymmetriccarbon atom, an optically active secondary alcohol [15-b] may besynthesized by subjecting an optically active secondary alcohol having anitrogenous or oxygenic functional group [15-a] to a deprotectingreaction to remove a protecting group R². Examples of the protectinggroup R² include acyl group, alkyloxycarbonyl group and optionallysubstituted benzyl group. For example, the conventional deprotectingmethod described in the literature accepted in the art (Greene, T. W.,et al., Protective Groups in Organic Synthesis, (Wiley-IntersciencePublication)) may be used. In particular, benzyl group and benzoyl groupare specifically mentioned as the protecting group R² of theα-aminoketone compounds included in [15-a] which are described in theabove as important intermediates for synthesizing α-aminoalcoholsdisclosed in WO 97/25311 and WO 99/01431 as being very useful fortreating and preventing diabetes, obesity, hyperlipidemia and the like.The benzoyl group may be removed, for example, by a hydrolysis reactionwith a base, such as sodium carbonate, potassium carbonate, sodiumhydroxide or potassium hydroxide.

[0915] The amount of the base to be added may be generally from about0.1 to about 10 mol for 1 mol of the benzoylamide. Generally, thereaction is preferably carried out in methanol, ethanol, tetrahydrofuranor 1,4-dioxane, or a water-mixed solvent thereof. The amount of suchsolvent to be used may be generally from about 1 to about 5 mL for 1 gof the benzoylamide. Generally, the reaction is preferably carried outat temperatures ranging from 20° C. to about 100° C., particularly, fromabout 50° C. to about 100° C., for example, for from 1 to 24 hours. Thebenzyl group may be removed by a hydrogenolysis reaction with a catalystsuch as palladium/carbon or palladium hydroxide/carbon. The amount ofthe catalyst to be used may be generally from about 5% to about 20% byweight with respect to the protected amine. Generally, the reaction ispreferably carried out in a solvent such as methanol, ethanol,tetrahydrofuran or acetic acid. The amount of the solvent to be used maybe from about 1 to about 50 mL for 1 g of the protected amine.Generally, the reaction may be preferably carried out at temperaturesranging from −10° C. to 50° C., particularly at room temperature, forexample, for from 3 to 10 hours. When the group R¹ contains a halogen,the deprotecting process is carried out according to the processdescribed in the literatures (M. Koreeda, et al., J. O. C., 49, p2081(1984) and S. Gubert, et al., Synthesis, 4, p318 (1991)).

[0916] The tert-butoxycarbonyl(Boc) group may be removed by reacting thecorresponding protected amine compound with a known mineral acid orLewis acid. Preferred examples of the known mineral acid and Lewis acidinclude hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid,trifluoroacetic acid, aluminium chloride, bromotrimethylsilane andiodotrimethylsilane, with hydrochloric acid being preferred. The amountof the mineral acid or Lewis acid to be added can generally vary fromabout the same molar amount to a solvent amount with respect to theprotected amine. This reaction can be carried out in a solvent. However,this reaction may also be preferably carried out using the above acid asa solvent. Examples of the solvent include a lower alcohol such asmethanol, ethanol or n-propanol, 1,4-dioxane, tetrahydrofuran,acetonitrile and dichloromethane, with methanol and ethanol beingpreferred. Generally, this reaction is preferably carried out attemperatures ranging from about −30° C. to about 100° C., particularlyfrom about 0° C. to about 30° C., for example, for 1 to 10 hours. Thebenzyloxycarbonyl group (Cbz group) may be removed by the same methodwith that for removing the benzyl group.

[0917] The amino-protecting groups may be sequentially or simultaneouslyremoved. For example, when R² is a benzyloxycarbonyl or benzyl group andR¹ is a benzyl-containing group, they can be removed under the samereaction condition and are preferably simultaneously removed. When R² isa tert-butoxycarbonyl or benzoyl group and R¹ is a benzyl-containinggroup, they are removed by sequential steps comprising, for example, thefirst removal of the tert-butoxycarbonyl or benzoyl group as R² followedby the removal of the benzyl group in R¹. The order of the removals isnot limited to the above and is preferably selected depending on thephysical properties and the like of the compound to be deprotected. Thecondition for removing each protecting group is as set forth above. Inaddition, these deprotections can be carried out with reference to theteachings of WO 97/25311.

[0918] Further, when A of the general formula (3) is CH₂OSiR⁵R⁶R⁷, asindicated in the reaction scheme (16):

[0919] wherein R¹, R⁵, R⁶, R⁷ and n are as defined above, and *represents an asymmetric carbon atom, an optically active diol [16-b]may be synthesized by subjecting an optically active secondary alcoholhaving an oxygenic functional group [16-a] to a deprotecting reaction toremove the silyl group. For example, the silyl group may be removed bythe conventional process, for example, described in the literatureaccepted in the art (Greene, T. W., et al., Protective Groups in OrganicSynthesis (Wiley-Interscience Publication)). Specifically, the processmay be a process comprising selectively removing the silyl group using afluoride anion-containing reagent, such as tetrabutylammonium fluoride.

[0920] Further, when A of the general formula (3) is CH(OR¹⁵)₂, asindicated in the reaction scheme (17):

[0921] wherein R¹, n and R¹⁵ are as defined above, and * represents anasymmetric carbon atom, an aldehyde group-containing optically activesecondary alcohol [17-b] may be synthesized by subjecting a ketalgroup-containing optically active secondary alcohol [17-a] to a processfor deprotecting such a ketal group. The ketal group may be removed bythe conventional method, for example, described in the literatureaccepted in the art (Greene, T. W., et al., Protective Groups in OrganicSynthesis (Wiley-Interscience Publication)).

[0922] Further, as indicated in the reaction scheme (18):

[0923] wherein R¹ and n are as defined above, and * represents anasymmetric carbon atom, an aldehyde form [17-b] may be converted into anoptically active diol [16-b] by a conventional aldehyde group-reducingreaction. The aldehyde group-reducing reaction is not limited as long asit does not affect the stereochemistry of the optically active secondaryhydroxyl group. Examples thereof include a process using ahydride-reducing agent, such as sodium borohydride or lithium aluminiumhydride; a catalytic hydrogenation reduction process using Pd/carbon asa catalyst; and a process using the catalyst of the present invention.

[0924] Further, as indicated in the reaction scheme (19):

[0925] wherein R¹ and n are as defined above, and * represents anasymmetric carbon atom, an amino group-containing optically activesecondary alcohol [15-b] may be synthesized by subjecting an aldehydeform [17-b] to an more abbreviated process which comprises preparing animine compound and a primary amine compound [6-a] represented by H₂NR³wherein R³ is as defined above, by a thermal dehydration treatment in asolvent such as methanol, ethanol or toluene, or by using variousdehydrating agents, followed by a conventional imine-reducing reaction.

[0926] Further, as indicated in the reaction scheme (20):

[0927] wherein R¹ and n are as defined above, B² represents a leavinggroup, and * represents an asymmetric carbon atom, an aminogroup-containing optically active secondary alcohols [15-b] or [20-b](wherein R¹, R², R³ and n are as defined above, and * represents anasymmetric carbon atom) may be prepared from an optically active diol[16-b] by subjecting the terminal primary hydroxyl group to aconventional reaction for converting such a primary hydroxyl group intoa leaving group B², and subjecting the leaving group B² to aconventional S_(N) ² type substitution reaction with a primary aminecompound [6-a] or with a secondary amine compound [4-b] (wherein R² andR³ are as defined above, provided that R² is other than acyl group andalkyloxycarbonyl group). The reaction for converting the primaryhydroxyl group into the leaving group B² may be a reaction comprisingconverting the primary hydroxyl group into the corresponding sulfonateby a reaction with methanesulfonyl chloride or p-toluenesulfonylchloride in an amount of from 1.0 to 1.1 mol for 1 mol of the hydroxylgroup in the presence of a base catalyst such as pyridine, NaHCO₃ orK₂CO₃ catalyst. Further, this sulfonate may be replaced with halogen bya reaction with NaBr, NaI or the like. Further, the primary hydroxylgroup may be directly converted into halogen by a reaction with from 1.0to 1.1 mol of carbon tetrabromide, N-bromosuccinimide or the like in thepresence of 1.5 mol of triphenylphosphine for 1 mol of the primaryhydroxyl group under a mild neutral condition.

[0928] Further, as indicated in the reaction scheme (21):

[0929] wherein R¹, R² and R³ are as defined above; provided that B²represents a leaving group, and R² is other than acyl group andalkyloxycarbonyl group; and * represents an asymmetric carbon atom, anα-amino group-containing optically active secondary alcohol [21-d] or[21-e] may be obtained from an optically active diol [16-b] wherein n is0 while maintaining the stereochemistry of *. That is, [21-d] or [21-e]may be obtained by subjecting the primary hydroxyl group to aconventional reaction for converting such a primary hydroxyl group intothe leaving group B² to yield the corresponding optically activesecondary alcohol having the leaving group B² [21-b]; converting theobtained alcohol [21-b] into the corresponding optically active epoxycompound [21-c] by a cyclization reaction in the presence of aconventional acid scavenger while maintaining the stereochemistry of *;and subjecting the optically active epoxy compound [21-c] to an epoxyring-opening reaction with a primary amine compound [6-a] or with asecondary amine compound [4-b] to yield the α-amino group-containingoptically active secondary alcohol [21-d] or [21-e] in which thestereochemistry of * is maintained.

EXAMPLES

[0930] The following examples further illustrate the processes of thepresent invention but are not intended to limit it in any way. In theexamples set forth below, all the reactions were carried out under anatmosphere of inert gas, such as argon gas or nitrogen gas unlessotherwise specifically mentioned. In the reactions, dehydrated anddegassed solvents were used. The ketone compound-hydrogenating reactionswere carried out under a pressurized hydrogen atmosphere in anautoclave. The determination of nuclear magnetic resonance spectrum(NMR) was carried out using GSX-270 (mfd. by NIHON DENSHI; ¹H-NMR, 270MHz; ¹³C-NMR, 67.5 MHz), JMN-GX 500 (mfd. by NIHON DENSHI; ¹H-NMR, 500MHz; ¹³C-NMR, 125 MHz; ³¹P-NMR, 202 MHz), α-400 (mfd. by NIHON BUNKO;¹H-NMR, 400 MHz; ¹³C-NMR, 100 MHz; ³¹P-NMR, 161.6 MHz), or Gemini-300(mfd. by Varian; ¹H-NMR, 300 MHz). Chemical shift, which is indicatedherein in 6(ppm), was determined using tetramethylsilane (TMS) as theinternal standard for ¹H-NMR or ¹³C-NMR where the signal from the protonor carbon was defined as δ=0. ³¹P-NMR was measured using a 10% solutionof phosphoric acid in heavy water where the signal therefrom was definedas δ=0. Coupling constant is indicated herein in J(Hz). The splittingpatterns are indicated using the following abbreviations: s (singlet), d(doublet), t (triplet), q (quartet), m (multiplet), and br (broad). Massspectrum (MS) was determined by the fast atom bombardment massspectrometry (FAB-MS) with JEOL-JMS-SX102. Specific rotation [α]_(D) wasmeasured using P-1010-GT (mfd. by NIHON BUNKO) with the solventspecifically mentioned herein and a cell (5 mmf×5 cm). Gaschromatography analysis was carried out using Type 6890 (mfd. by HEWLETTPACKARD) with capillary column and helium pressure specificallymentioned herein and detection was carried out using FID. Highperformance liquid chromatography measurement was carried out using TypePU-980 pump (mfd. by NIHON BUNKO) and Type UV-970 UV detector (mfd. byNIHON BUNKO) with column, solvent, flow rate and UV detecting wavelength each specifically mentioned herein. Silica gel thin layerchromatography (TLC) and silica gel preparative thin layerchromatography (PTLC) used were Kieselgel 60 F254 Art.1.05719 (mfd. byMerck; thickness 0.25 mm) and Art.1.05715 (mfd. by Merck; thickness 0.25mm) respectively. Preparative column chromatography used was Kieselgel60 (mfd. by Merck; 230-400 mesh). Argon gas used was a purified argongas obtained by passing a standard argon gas (purity 99%) through acolumn which had been load with BASF catalyst R³-11 and heated to 80° C.Hydrogen gas used was a hydrogen gas (purity 99.99999%) manufactured byNIPPON SANSO. Toluene used was a toluene preserved in a Schlenk tubewhich had been obtained by distillation from sodium-benzophenone ketylunder an argon atmosphere. N,N-Dimethylformamide (DMF) andN,N-dimethylacetamide (DMA) used were those preserved in Schlenk tubesrespectively which had been obtained by distillation from calciumhydride under an argon atmosphere, unless otherwise specificallymentioned. Tetrahydrofuran (THF) used was a tetrahydrofuran freshlyobtained by distillation from sodium-benzophenone ketyl under an argonatmosphere with a distillation column. 2-Propanol and dichloromethaneused were those freshly obtained respectively by distillation fromcalcium hydride under a nitrogen atmosphere with a distillation column.

Example 1

[0931] Synthesis of Trans-RuCl₂[(S)-xylbinap][(S)-daipen] (Complex(S,S)-1)

[0932] [RuCl₂(benzene)]₂ (261 mg, 0.522 mmol; mfd. by Aldrich) and(S)-Xyl-BINAP (805 mg, 1.10 mmol; synthesized by the process disclosedin JP-B-07-682609) were measured into a 75 mL Schlenk type reaction tubeequipped with a teflon-coated stirrer. After air in the tube was reducedevacuated, argon was then introduced. DMF (2 mL) was added with asyringe and the resulting mixture was heated on an oil bath at 100° C.under an argon atmosphere for 10 minutes. The reaction solution wasallowed to cool down to room temperature and DMF was then distilled offunder reduced pressure (1 mmHg). To the thus obtained dark reddish-brownRuCl₂[(S)-xylbinap](dmf)_(n), (S)-DAIPEN (414 mg, 1.32 mmol; mfd. byKANTO KAGAKU) and dichloromethane (2 mL) were added under an argonstream, followed by stirring at 25° C. for 30 minutes. To a green crudeproduct obtained by distilling dichloromethane off under reducedpressure (1 mmHg), hexane (5 mL) was added. The resulting yellow productwas dissolved as much as possible and the green impurity was removed bysuction filtration. The yellow solution obtained by the suctionfiltration was concentrated until the complex was deposited. As aresult, a solid was obtained.

[0933] This procedure was repeated twice. The thus obtained solids werecollected by filtration and dried under reduced pressure (1 mmHg) togive Complex (S,S)-1 (803 mg, 0.658 mmol; yield 63%) as a yellowcrystal.

[0934]¹H-NMR (400 MHz, C₆D₆) δ 0.06 (d, 3H, J=6.6), 0.61 (d, 3H, J=6.8),1.74 (s, 6H), 1.75 (included in the peaks at δ 1.74 and 1.77, 1H), 1.77(s, 6H), 2.80 (m, 1H), 3.00 (m, 1H), 3.19 (s, 3H), 3.38 (s, 3H), 3.80(m, 1H), 4.40 (m, 1H), 5.09 (d, 1H, J=13.4), 5.90-9.00 (m, 32H);

[0935]³¹P-NMR (202 MHz, CDCl₃) δ 44.1 (d, J=36.4), 46.7 (d, J=36.4).

Example 2

[0936] Synthesis of Trans-RuCl₂[(S)-xylbinap][(S,S)-dpen] (Complex(S,SS)-2)

[0937] The title compound was synthesized using [RuCl₂(benzene)]₂ (261mg, 0.522 mmol), (S)-Xyl-BINAP(805 mg, 1.10 mmol) and (S,S)-DPEN (279mg, 1.32 mmol; mfd. by KANKYO KAGAKU CENTER) according to the procedureof Example 1, with the exception that the crude product was dissolved ina dichloromethane/diethyl ether solution (3 mL; volume ratio 1/2) andthe resulting solution was passed through a column charged with silicagel (10 g) to remove impurities. The yellow solution obtained as aformer fraction was concentrated until the complex was deposited. Theresulting solid was collected by filtration and dried under reducedpressure (1 mmHg) to give Complex (S,SS)-2 (782 mg, 0.699 mmol; yield67%) as a yellow crystal.

[0938]¹H-NMR (400 MHz, C₆D₆) δ 1.80 (s, 12H), 2.08 (s, 12H), 3.45 (m,2H), 3.53 (m, 2H), 4.60 (m, 2H), 5.90-9.00 (m, 34H);

[0939]³¹P-NMR (202 MHz, CDCl₃) δ 45.0.

Example 3

[0940] Synthesis of Trans-RuCl₂[(S)-xylbinap][(S,S)-cyclohexanediamine](Complex (S,SS)-3)

[0941] The title compound was synthesized using [RuCl₂(benzene)]₂ (130mg, 0.261 mmol), (S)-Xyl-BINAP (403 mg, 0.548 mmol) and(S,S)-1,2-cyclohexanediamine (75 mg, 0.657 mmol; mfd. by Wako PureChemical Industries) according to the procedure of Example 1, withexception that the crude product was dissolved in adichloromethane/diethyl ether solution (5 mL; volume ratio 1/2) and theresulting solution was passed through a column charged with silica gel(5 g) to remove impurities. The brown solution obtained as a formerfraction was concentrated until the complex was deposited. The resultingsolid was collected filtration and dried under reduced pressure (1 mmHg)to give Complex (S,SS)-3 (480 mg, 0.470 mmol; yield 90%) as a yellowcrystal.

[0942]¹H-NMR (400 MHz, C₆D₆) δ 0.50 (m, 4H), 1.00 (m, 2H), 1.10 (m, 2H),1.80 (s, 12H), 2.10 (m, 2H), 2.18 (s, 12H), 2.70 (m, 2H), 3.00 (br-d,2H, J=8.6), 5.90-9.0 (m, 24H);

[0943]³¹P-NMR (202 MHz, CDCl₃) δ 44.7.

Example 4

[0944] Synthesis of Trans-RuCl₂[(S)-xylbinap][(S)-damen] (Complex(S,S)-4)

[0945] The title compound was synthesized from [RuCl₂(benzene)]₂ (25.5mg, 0.05 mmol), (S)-Xyl-BINAP (73.49 mg, 0.10 mmol) and (S)-DAMEN (31.5mg, 0.11 mmol; synthesized according to the process described in theliterature: Burrows C. J., et al., Tetrahedron Letters, 34(12), pp.1905-1908 (1993)), with the exception that the crude product wasdissolved in a dichloromethane/diethyl ether solution (5 mL; volumeratio 1:2) and the resulting solution was passed through a columncharged with silica gel (5 g) to remove impurities. The brown solutionobtained as an advance product was concentrated until the complex wasdeposited. The resulting solid was collected by filtration and driedunder reduced pressure (1 mmHg) to givetrans-RuCl₂[(S)-xylbinap][(S)-damen] (78.7 mg, 0.066 mmol; yield 66%) asa yellow crystal.

[0946] 1H-NMR (400 MHz, CDCl₃) δ 0.68 (d, 3H, J=6.8), 1.74 (s, 6H), 1.75(s, 6H), 2.08 (s, 6H), 2.30 (s, 6H), 2.65 (m, 1H), 2.74 (m, 1H), 3.39(m, 1H), 3.75 (s, 3H), 3.83 (s, 3H), 4.05 (m, 1H), 4.80 (br, 1H), 5.88(d, 2H, J=9.5), 6.06 (t, 2H, J=8.3), 6.60-7.80 (m, 26H), 8.30 (m, 2H);

[0947]³¹P-NMR (161.6 MHz, CDCl₃) δ 43.4 (d, J=36.9), 44.0 (d, J=36.9).

[0948] Examples of ruthenium/bidentate phosphine/diamine complex whichmay be synthesized according to the procedure of Example 1 are indicatedas the general formula (22).

[0949] Example of Ru Complex:

Example 5

[0950] Asymmetric Hydrogenation of 3-dimethylaminopropiophenone

[0951] Trans-RuCl₂[(S)-xylbinap][(S)-daipen] (Complex (S,S)-1; 7.3 mg, 6μmol) was measured into a 500 mL glass autoclave equipped with ateflon-coated stirrer. After air in the autoclave was evacuated, argonwas then introduced. 2-Propanol (30 mL) and a solution of potassiumtert-butoxide in 2-methyl-2-propanol (1.0 M solution, 60 μL, 60 μmol;mfd. by Aldrich), which had been previously degassed by argon-bubbling,were added with a syringe under an argon stream.

[0952] The thus obtained solution was degassed by applying five timesthe pressure-reducing/argon-introducing procedure to the solution withstirring. The solution was stirred on an oil bath at 60° C. for 30minutes. After the oil bath was removed and the solution was allowed tocool down to room temperature, 3-dimethylaminopropiophenone (10.6 g, 60mmol; synthesized according to the process described in the literature:Maxwell, C. E., Org. Synthesis, 1955, Coll. Vol. 3, pp. 305-306) and2-propanol (30 mL) which had been previously degassed by argon-bubbling,were added with a syringe under an argon stream. The thus obtainedsolution was degassed by applying five times thepressure-reducing/argon-introducing procedure to the solution withstirring. A hydrogen cylinder was connected to the autoclave using ahydrogen-feeding pipe and the atmosphere within the feeding pipe wasreplaced with hydrogen gas (2 atm) five times. After the pressure in theautoclave was increased to 5 atm, the hydrogen gas was carefullydischarged until the pressure was lowered to 2 atm. This procedure wasrepeated seven times. The pressure of hydrogen gas was then increased to8 atm, followed by vigorous stirring at 25° C. for 5 hours. After thereaction was completed, the thus obtained solution was concentratedunder reduced pressure to give (R)-1-phenyl-3-dimethylaminopropan-1-ol(97.5% ee; yield 96% as measured by ¹H-NMR using methyl propionate asthe internal standard).

[0953] The obtained product was subjected to an abbreviated distillationtreatment with Kugel Rohr to give(R)-1-phenyl-3-dimethylaminopropan-1-ol (9.84 g, yield 93%, purity 98%)as a colorless oil.

[0954]¹H-NMR (500 MHz, CDCl₃) δ 1.76-1.87 (m, 2H), 2.30 (s, 6H),2.45-2.49 (m, 2H), 2.63-2.49 (m, 2H), 4.93 (dd, 1H, J=7.8, 3.9), 6.86(s, 1H), 7.22-7.42 (m, 5H);

[0955]¹³C-NMR (125 MHz, CDCl₃) δ 34.5, 45.3, 58.5, 75.8, 125.6, 126.8,128.2, 145.1.

[0956] The enantiomer excess was determined by means of HPLC analysis.

[0957] Chiral Column: CHIRALCEL OD (4.6 mm ID×250 mm; mfd. by Daicel);

[0958] Mobile phase: hexane/2-propanol (9/1);

[0959] Column temperature: 30° C.;

[0960] UV wave length: 254 nm;

[0961] Flow rate: 0.5 mL/min;

[0962] Retention time:

[0963] (R)-1-phenyl-3-dimethylaminopropan-1-ol: 12.5 min (98.75%)

[0964] (S)-1-phenyl-3-dimethylaminopropan-1-ol: 16.2 min (1.25%).

[0965] The absolute structure was determined as R-form by comparing thespecific rotation with the known specific rotation disclosed in thefollowing reference.

[0966] Actual measurement value: [α]²⁶ _(D)=+32.0 (c=1.695, CH₃OH)

[0967] Literature data of R-form: [α]_(D)+27.6 (c=1.61, CH₃OH)

[0968] Reference: Andrisano, R.; Angeloni, A. S.; Marzocchi, S.,Tetrahedron, 1973, 29, pp. 913-916.

Comparative Example 1

[0969] The procedure of this comparative example is different from thatof Example 5. This comparative example was carried out by a procedurecomprising no step of previously preparing an activated catalyst speciesusing a base and Complex (S,S)-1 which is a catalyst precursor. In thiscase, the decomposition of 3-dimethylamino-propiophenone took precedenceover its hydrogenation. Both purity and yield of the thus obtained(R)-1-phenyl-3-dimethylaminopropan-1-ol in the asymmetrically reducedform were lowered. The said comparative example will be described inmore detail.

[0970] Complex (S,S)-1 (1.5 mg, 1.25 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. After air in theautoclave was evacuated, argon was then introduced.3-Dimethylaminopropiophenone (443 mg, 2.5 mmol), 2-propanol (2.5 mL),and a solution of potassium tert-butoxide in 2-methyl-2-propanol (1.0 Msolution, 25 mL, 25 mmol; mfd. by Aldrich) which had been previouslydegassed by argon-bubbling, were added with a syringe under an argonstream. The thus obtained solution was degassed by applying five timesthe pressure-reducing/argon-introducing procedure to the solution withstirring.

[0971] A hydrogen cylinder was connected to the autoclave using ahydrogen-feeding pipe and the atmosphere within the feeding pipe wasreplaced with hydrogen gas (2 atm) five times. After the pressure in theautoclave was increased to 5 atm, the hydrogen gas was carefullydischarged until the pressure was lowered to 2 atm. This procedure wasrepeated seven times. The pressure of hydrogen gas was then increased to8 atm, followed by vigorous stirring at 25° C. for 3 hours. After thereaction solution was concentrated under reduced pressure, the residuewas subjected to a silica gel column chromatography treatment (silicagel 20 g; solvent: dichloromethane) to give(R)-1-phenyl-3-dimethylaminopropan-1-ol (102 mg, 0.6 mmol, yield 24%,97% ee).

[0972] Therefore, the most preferred example of the present invention isa process according to the procedure of Example 5 comprising previouslyactivating a catalyst by reacting a complex with a base at 60° C. for 30minutes or more, and then conducting hydrogenation of a substrate byadding the substrate and pressurizing with hydrogen. In the following,Examples 6 to 24, Example 26 and Example 28 were carried out accordingto the procedure of Example 5.

Example 6

[0973] Asymmetric Hydrogenation of 2-dimethylaminoacetophenone(Intermediate 7: Free-Form)

[0974] Complex (R,R-1) (6.1 mg, 5 μmol; synthesized using R-form ligandsaccording to the procedure of Example 1) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing 2-dimethylaminoacetophenone (1.63 g, 10 mmol; freshly obtained byneutralizing a hydrobromide salt of Intermediate 7 with a 0.1 Npotassium hydroxide solution, and extracting the thus neutralizedmaterial with diethyl ether followed by drying treatment under reducedpressure), a 1.0 M solution of potassium tert-butoxide in2-methyl-2-propanol (100 μL, 0.1 mmol; mfd. by Aldrich) and 2-propanol(10 mL) with vigorous stirring under a hydrogen atmosphere at 8 atm at25° C. for 12 hours. The resulting reaction mixture was then subjectedto an abbreviated distillation treatment with Kugel Rohr to give(R)-1-phenyl-2-dimethylaminoethanol (93% ee, 1.49 g, yield 90%) as acolorless oil.

[0975]¹H-NMR (400 MHz, CDCl₃) δ 2.31-2.51 (m, 8H), 4.69 (dd, 1H, J=10.8,3.2), 7.25-7.39 (m, 5H).

[0976] The enantiomer excess was determined by means of HPLC analysis ofan ester-form obtained by benzoylating the thus obtained product.

[0977] Chiral Column: CHIRALCEL OD (4.6 mm ID X 250 mm; mfd. by Daicel);

[0978] Mobile phase: hexane/2-propanol (49/1);

[0979] Column temperature: 40° C.;

[0980] UV wave length: 254 nm;

[0981] Flow rate: 0.3 mL/min;

[0982] Retention time:

[0983] Benzoate of (S)-1-phenyl-2-dimethylaminoethanol: 16.0 min (3.3%)

[0984] Benzoate of (R)-1-phenyl-2-dimethylaminoethanol: 18.2 min (96.7%)

[0985] The absolute structure was determined as R-form by comparing thespecific rotation with the known specific rotation of(R)-1-phenyl-2-dimethylaminoethanol hydrochloride disclosed in thefollowing reference.

[0986] Actual measurement value: [α]²⁷ _(D)=−64.0 (c=0.635, C₂H₅OH)Literature data of R-form: [α]^(23.5) _(D)=−78.9(c=0.985, C₂H₅OH)

[0987] [α]_(D) reference: Chan, M. M-L.; Robinson, J. B., J. Med. Chem.,1974, 17, p. 1057.

Example 7

[0988] Asymmetric Hydrogenation of Dimethylaminoacetone

[0989] Complex (R,R)-1 (1.5 mg, 1.25 μmol; synthesized using R-formligands according to the procedure of Example 1) was measured into a 100mL glass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing dimethylaminoacetone (253 mg, 2.5 mmol; mfd. by Aldrich), a 1.0 Msolution of potassium tert-butoxide in 2-methyl-2-propanol (20 μL, 20μmol; mfd. by Aldrich) and 2-propanol (2.5 mL) with vigorous stirringunder a hydrogen atmosphere at 8 atm at 25° C. for 4 hours. After thereaction was completed, the thus obtained solution was diluted withether, and a 1.0 M solution of hydrogen chloride in ether (3 mL, 3 mmol;mfd. by Aldrich) was added. The resulting mixture was concentrated underreduced pressure to give 1-dimethylamino-2-propanol monohydrochloride.The yield was 99% as measured by ¹H-NMR analysis.

[0990]¹H-NMR (400 MHz, DMSO-d₆) δ 1.10 (d, 3H, J=6.0), 2.77 (dd, 6H,J=12.8, 4.8), 2.90-2.97 (m, 1H), 3.02-3.08 (m, 1H), 4.03-4.11 (m, 1H),9.95 (br, 1H).

[0991] To the thus obtained 1-dimethylamino-2-propanol monohydrochloridewere added dichloromethane (10 mL), distilled water (200 mL) and sodiumhydroxide (120 mg, 3 mmol; mfd. by Nacalai Tesque). The resultingmixture was stirred for 2 hours. dichloromethane was distilled off underreduced pressure, followed by an abbreviated distillation treatment withKugel Rohr. The thus obtained oil was diluted with dichloromethane,dried over anhydrous sodium sulfate and then filtered. The filtrate wasconcentrated under reduced pressure to give(S)-1-dimethylamino-2-propanol (92% ee, 205 mg, 1.99 mmol, yield 79%) asa light yellow oil.

[0992]¹H-NMR (400 MHz, CDCl₃) δ 1.13 (d, 3H, J=6.4), 2.12-2.27 (m, 8H),3.77-3.80 (m, 1H).

[0993] The enantiomer excess was determined based on the area ratio ofthe methine proton at 2-position according to ¹H NMR analysis using ashift reagent. The measurement was carried out using1-dimethylamino-2-propanol (22 mg, 0.21 mmol) and europiumtris[3-heptafluoropropylhydroxymethylene-(+)-camphorate] (200 mg, 0.17mmol) in CDCl₃. The absolute structure was determined as S-form bycomparing the specific rotation with the known specific rotation of(R)-1-dimethylamino-2-propanol disclosed in the following reference.

[0994] Actual measurement value: [α]²⁷ _(D)=+21.1 (c=1.006, CH₃OH);

[0995] Literature data of R-form: [α]_(D)=−23.7 (c=1.11, CH₃OH);

[0996] [α]_(D) reference: Tomita, L. D.; Klabunovskii, E. I.; Petrov,Yu. I.; Kretova, L. A.; Kholdyakov, N. I.; Antonova, T. A.; Cherkasova,E. M., Bull. Acad. Sci. USSR. Div. Chem. Sci. (Engl. Transl.), 1971, 20,p. 2063.

Example 8

[0997] Asymmetric Hydrogenation of 2-[(Methyl)(Phenyl)amino]acetone(Intermediate 8) Complex (R,R-1) (1.5 mg, 1.25 μmol) was measured into a

[0998] 100 mL glass autoclave equipped with a teflon-coated stirrer. Anasymmetric hydrogenation according to the procedure of Example 5 wascarried out using Intermediate 8 (408 mg, 2.5 mmol), a solution ofpotassium tert-butoxide in 2-methyl-2-propanol (1.0 M solution, 25 μL,25 μmol; mfd. by Aldrich) and 2-propanol (2.5 mL) with vigorous stirringunder a hydrogen atmosphere at 8 atm at 25° C. for 13 hours. After thereaction was completed, the thus obtained solution was concentratedunder reduced pressure and compounds derived from the complex wasremoved by a silica gel chromatography treatment (silica gel 10 g;solvent: diethyl ether) to give 1-[(methyl)(phenyl)amino]-2-propanol(81% ee, 384 mg, 2.32 mmol, yield 93%) as a colorless oil.

[0999]¹H-NMR (270 MHz, CDCl₃) δ 1.23 (d, 3H, J=12.7), 2.18 (s, 1H), 2.98(s, 3H), 3.23 (d, 2H, J=6.5), 4.06-4.18 (m, 1H), 6.74-6.85 (m, 3H),7.20-7.29 (m, 2H).

[1000] The enantiomer excess was determined by means of HPLC analysis.

[1001] Chiral Column: CHIRALCEL OD (4.6 mm ID×250 mm; mfd. by Daicel);

[1002] Mobile phase: hexane/2-propanol (9/1);

[1003] Column temperature: 30° C.;

[1004] UV wave length: 254 nm;

[1005] Flow rate: 0.5 mL/min;

[1006] Retention time:

[1007] (S)-1-[(methyl)(phenyl)amino]-2-propanol: 14.7 min (90.7%)

[1008] (R)-1-[(methyl)(phenyl)amino]-2-propanol: 22.2 min (9.3%)

[1009] The absolute structure was determined by comparing the specificrotation with the specific rotation of a separately synthesized(S)-1-[(methyl)(phenyl)amino]-2-propanol.

[1010] Actual measurement value of the asymmetrically hydrogenatedproduct: [α]²³ _(D)=+19.0 (c=0.545, CH₃OH)

[1011] Specific rotation of separately synthesized(S)-1-[(methyl)-(phenyl)amino]-2-propanol (>99% ee) having a knownabsolute structure: [α]²³ _(D)=+26.3 (c=0.538, CH₃OH)

[1012] A process for the preparation of the separately synthesized(S)-1-[(methyl)(phenyl)-amino]-2-propanol will be described below.

[1013] Synthesis of (S)-1-[(Methyl)(Phenyl)amino]-2-propanol

[1014] Alumina (26 g; mfd. by Merck), diethyl ether (80 mL) andN-methylaniline (1.07 g, 10 mmol; mfd. by TOKYO KASEI) were added to a100 mL recovery flask equipped with a teflon-coated stirrer. To theresulting mixture, (S)-propylene oxide (140 μL, 2 mmol; mfd. by TOKYOKASEI) diluted with diethyl ether (2 mL) was added dropwise withvigorous stirring. After stirring at 25° C. for 6 hours, the reactionliquid was filtered to give a solution, which was then concentratedunder reduced pressure. The residue was subjected to a silica gelchromatography treatment (silica gel 70 g; 1:3 ethyl acetate/hexane) togive as the first fraction, (S)-1-[(methyl)(phenyl)amino]-2-propanol(123 mg, 0.746 mmol, yield 37%) as a colorless oil.

[1015]¹H-NMR (270 MHz, CDCl₃) δ 1.23 (d, 3H, J=12.7), 2.18 (s, 1H), 2.98(s, 3H), 3.23 (d, 2H, J=6.5 Hz), 4.06-4.18 (m, 1H), 6.74-6.85 (m, 3H),7.20-7.29 (m, 2H);

[1016] [α]²³ _(D)=+26.3 (c=0.538, CH₃OH), >99% ee(S).

Example 9

[1017] Asymmetric Hydrogenation of2-[(benzoyl)(3,4-dimethoxyphenethyl)amino]-4′-benzyloxyacetophenone

[1018] Complex (R,R-1) (1.5 mg, 1.25 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing2-[(benzoyl)(3,4-dimethoxyphenethyl)amino]-4′-benzyloxyacetophenone(1.27 g, 2.5 mmol; prepared according to the method described inYAKUGAKU ZASSHI, 106(1), pp. 80-89(1986)), a solution of potassiumtert-butoxide in 2-methyl-2-propanol (1.0 M solution, 50 μL, 50 μmol;mfd. by Aldrich) and 2-propanol (2.5 mL) with vigorous stirring under ahydrogen atmosphere at 8 atm at 25° C. for 24 hours.

[1019] After the reaction was completed, the thus obtained solution wasconcentrated under reduced pressure and compounds derived from thecomplex was removed by a silica gel chromatography treatment (silica gel5 g; solvent: ethyl acetate) to give(R)-2-[(benzoyl)-(3,4-dimethoxyphenethyl)amino]-1-(4′-benzyloxyphenyl)ethanol(97% ee, 1.28 g, 2.5 mmol, yield 100%) as a white solid. The enantiomerexcess was determined by means of HPLC analysis.

[1020] Chiral Column: CHIRALPAK AD (4.6 mm ID×250 mm; mfd. by Daicel);

[1021] Mobile phase: hexane/2-propanol (3/1);

[1022] Column temperature: 40° C.;

[1023] UV wave length: 254 nm;

[1024] Flow rate: 1 mL/min;

[1025] Retention time:

[1026](R)-2-[(benzoyl)(3,4-dimethoxyphenethyl)amino]-1-(4′-benzyloxyphenyl)ethanol:11.7 min (98.6%);

[1027](S)-2-[(benzoyl)(3,4-dimethoxyphenethyl)amino]-1-(4′-benzyloxyphenyl)ethanol:14.8 min (1.4%).

[1028] The absolute structure was determined after removing the benzoylgroup. The absolute structure-determining process will be describedbelow.

[1029] Synthesis of(R)-1-(4-benzyloxyphenyl)-2-[2-(3,4-dimethoxyphenyl)ethylamino]ethanolMonohydrochloride

[1030] To a 50 mL recovery flask equipped with a teflon-coated stirrerand a reflux column,(R)-2-[(benzoyl)(3,4-dimethoxyphenethyl)amino]-1-(4′-benzyloxyphenyl)ethanol(1.28 g, 2.5 mmol; obtained in Example 9), ethanol (25 mL), distilledwater (2.5 mL) and 85% potassium hydroxide (pellet, 660 mg, 10 mmol;mfd. by Nacalai Tesque). The resulting mixture was placed on an oil bathand refluxed for 8 hours. After allowing to cool down to roomtemperature, the mixture was extracted with distilled water and ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate and then filtered. The thus obtained solutionwas concentrated under reduced pressure. The residue was diluted withdiethyl ether (30 mL). After a solution of hydrogen chloride in ether (1M solution, 3 mL, 3 mmol; mfd. by Aldrich) was added dropwise, theresulting mixture was concentrated under reduced pressure to give thetitle debenzoylated compound,(R)-1-(4-benzyloxyphenyl)-2-[2-(3,4-dimethoxyphenyl)ethylamino]ethanolmonohydrochloride (1.10 g, 2.48 mmol, yield 99%).

[1031] This was recrystalized from ethanol to give an optically pure(R)-1-(4-benzyloxyphenyl)-2-[2-(3,4-dimethoxyphenyl)ethylamino]-ethanolmonohydrochloride (927 mg, 2.09 mmol, yield 84%).

[1032]¹H-NMR (400 MHz, DMSO-d₆) δ 2.68-2.85 (m, 6H), 3.71 (s, 3H), 3.73(s, 3H), 4.63 (m, 1H), 5.09 (s, 2H), 6.70-6.72 (m, 1H), 6.80-6.86 (m,2H), 6.96 (d, 2H, J=8.4), 7.24 (d, 2H, J=8.8), 7.30-7.44 (m, 5H).

[1033] The enantiomer excess was determined by means of optically activeHPLC analysis of free amine form of1-(4′-benzyloxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol. HPLC

[1034] Column: CHIRALPAK AD (4.6 mm ID×250 mm; mfd. by Daicel);

[1035] Solvent: hexane/2-propanol (4/1);

[1036] Temperature: 40° C.;

[1037] UV wave length: 254 nm;

[1038] Flow rate: 0.5 mL/min;

[1039] Retention time:

[1040](R)-1-(4′-benzyloxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol:

[1041] 19.2 min (100%);

[1042](S)-1-(4′-benzyloxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol:

[1043] 21.2 min (0%).

[1044] Actual measurement value: [α]²⁵ _(D)=−30.5 (c=0.96, CH₃OH);

[1045] Literature data of R-form: [α]_(D)=−300.1 (c=1, CH₃OH);

[1046] [α]_(D) reference: Kawaguchi, T.; Saito, K.; Matsuki, K.;Iwakuma, T.; Takeda, M., Chem. Pharm. Bull., 1993, 41, p. 639.

Example 10

[1047] Asymmetric Hydrogenation of4′-fluoro-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butyrophenone(S/C=2000, 0.5 M)

[1048] Complex (S,S-1) (1.5 mg, 1.25 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing4′-fluoro-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butyrophenone (866mg, 2.5 mmol; mfd. by the process described in Yevich, J. P.; New, J.S.; Lobeck, W. G.; Dextraze, P.; Bernstein, E.; Taylor, D. P.; Yocca, F.D.; Eison, M. S.; Temple, Jr. D. L., J. Med. Chem., 1992, 35, p. 4516),a solution of potassium tert-butoxide in 2-methyl-2-propanol (1.0 Msolution, 50 μL, 50 μmol; mfd. by Aldrich) and 2-propanol (5 mL) withvigorous stirring under a hydrogen atmosphere at 8 atm at 25° C. for 12hours.

[1049] After the reaction was completed, the thus obtained solution wasconcentrated under reduced pressure and compounds derived from thecomplex was removed by a silica gel chromatography treatment (silica gel5 g; solvent: ethyl acetate) to give(R)-1-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol(99% ee, 843 mg, 2.42 mmol, yield 97%) as a white solid.

[1050]¹H-NMR (400 MHz, CDCl₃) δ 1.65-1.98 (m, 4H), 2.44-2.65 (m, 6H),3.83 (m, 2H), 4.66 (dd, 1H, J=7.6, 2.4), 6.98-7.02 (m, 2H), 7.32-7.35(m, 2H), 8.19 (s, 2H);

[1051]¹³C-NMR (100 MHz, CDCl₃) δ 23.56, 39.52, 43.81, 52.73, 58.74,72.95, 114.8 (J_(CF)=21.0), 127.1 (J_(CF)=7.7), 141.3 (J_(CF)=2.8),145.0 (J_(CF)=21.4), 151.6 (J_(CF)=247.1), 158.7, 161.7 (J_(CF)=243.0).

[1052] The enantiomer excess was determined by means of HPLC analysis.

[1053] Chiral Column: CHIRALPAK AD (4.6 mm ID×250 mm; mfd. by Daicel);

[1054] Mobile phase: hexane/2-propanol (19/1);

[1055] Column temperature: 40° C.;

[1056] UV wave length: 254 nm;

[1057] Flow rate: 0.5 mL/min;

[1058] Retention time:

[1059](S)-1-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol:27.4 min (0.3%);

[1060](R)-1-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol:29.4 min (99.7%)

[1061] The absolute structure was determined as R-form by comparing thespecific rotation with the known specific rotation disclosed in thefollowing reference.

[1062] Actual measurement value: [α]²⁵ _(D)=+14.6 (c=1.05, CH₃OH);

[1063] Literature data of R-form (>99.9% ee): [α]²⁵ _(D)+14.3 (c=0.53,CH₃OH);

[1064] [α]_(D) reference: Yevich, J. P.; New, J. S.; Lobeck, W. G.;Dextraze, P.; Bernstein, E.; Taylor, D. P.; Yocca, F. D.; Eison, M. S.;Temple, Jr. D. L., J. Med. Chem., 1992, 35, p. 4516.

Example 11

[1065] Asymmetric Hydrogenation of4′-fluoro-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butyrophenone(S/C=2000, 1 M)

[1066] The procedure of Example 10 was repeated with the exception thatthe reactant concentrations were altered as follows. Catalyst: Complex(R,R)-1 (1.5 mg, 1.25 μmol); Substrate:4′-fluoro-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butyrophenone (866mg, 2.5 mmol); Solvent: 2-propanol (2.5 mL); Base: a solution ofpotassium tert-butoxide in 2-methyl-2-propanol (1.0 M solution, 50 μL,50 [mol; mfd. by Aldrich); Hydrogen pressure: 8 atm; Temperature: 25°C.; Reaction time: 32 hours; Isolated yield: 78%; Enantiomer excess:99%; Absolute structure: S.

Example 12

[1067] Asymmetric hydrogenation of4′-fluoro-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butyrophenone(S/C=2000, 1 M)

[1068] The procedure of Example 10 was repeated with the exception thatalterations were made as follows. Catalyst:trans-RuCl₂[(R)-tolbinap][(R,R)-dpen] (1.2 mg, 1.25 μmol; synthesizedfrom (R)-Tol-BIANP (mfd. by AZMAX), (R,R)-DPEN (mfd. by KANKYO KAGAKUCENTER) and [RuCl₂(benzene)]₂ (mfd. by Aldrich) according to theprocedure of Example 1); Substrate:4′-fluoro-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butyrophenone (866mg, 2.5 mmol); Solvent: 2-propanol (2.5 mL); Base: a solution ofpotassium tert-butoxide in 2-methyl-2-propanol (1.0 M solution, 50 μL,50 μmol; mfd. by Aldrich); Hydrogen pressure: 8 atm; Temperature: 25°C.; Reaction time: 16 hours; Isolated yield: 78%; Enantiomer excess:74%; Absolute structure: S.

Example 13

[1069] Asymmetric Hydrogenation of4′-fluoro-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butyrophenone(S/C=10000, 0.5 M)

[1070] Complex (S,S)-1 (1.2 mg, 1.0 μmol) was measured into a 500 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing4′-fluoro-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butyrophenone(3.46 g, 10 mmol), a solution of potassium tert-butoxide in2-methyl-2-propanol (1.0 M solution, 200 μL, 0.2 mmol; mfd. by Aldrich)and 2-propanol (20 mL) with vigorous stirring under a hydrogenatmosphere at 8 atm at 25° C. for 32 hours. After the reaction wascompleted, the thus obtained solution was concentrated under reducedpressure and subjected to a silica gel chromatography treatment (silicagel, 170 g; solvent: benzene/ethyl acetate (1/1) to ethyl acetate) togive as the second fraction(R)-1-(4-fluorophenyl)-4(5-fluoro=2=pyrimidinyl)-1-piperazinebutanol(99% ee, 3.29 g, 9.45 mmol, yield 94.5%) as a white solid. This wasrecrystalized twice from ethanol to give an optically pure(R)-1-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol(2.55 g, 7.32 mmol, yield 73%) as a white solid.

Example 14

[1071] Asymmetric Hydrogenation of Benzyloxyacetone (Intermediate 9)

[1072] Complex (S,S)-1 (1.5 mg, 1.25 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing Intermediate 9 (411 mg, 2.5 mmol), a solution of potassiumtert-butoxide in 2-methyl-2-propanol (1.0 M solution, 20 μL, 20 μmol;mfd. by Aldrich) and 2-propanol (2.5 mL) with vigorous stirring under ahydrogen atmosphere at 8 atm at 25° C. for 13 hours.

[1073] After the reaction was completed, the thus obtained solution wasconcentrated under reduced pressure and compounds derived from thecomplex were removed by a silica gel chromatography treatment (silicagel 5 g; solvent: diethyl ether) to give (R)-1-benzyloxy-2-propanol (79%ee, 398 mg, 2.39 mmol, yield 96%) as a colorless oil.

[1074]¹H-NMR (400 MHz, CDCl₃) δ 1.15 (d, 3H, J=6.0), 2.45 (s, 1H), 3.29(dd, 1H, J=9.2, 7.6), 3.47 (dd, 1H, J=9.2, 3.2), 3.96-4.04 (m, 1H), 4.56(s, 2H), 7.27-7.38 (m, 5H);

[1075]¹³C-NMR (100 MHz, CDCl₃), d 18.60, 66.48, 73.29, 75.29, 127.71,127.76, 128.44, 137.95.

[1076] The enantiomer excess was determined by means of HPLC analysis.

[1077] Chiral Column: CHIRALCEL OD (4.6 mm ID×250 mm; mfd. by Daicel);

[1078] Mobile phase: hexane/2-propanol (95/5);

[1079] Column temperature: 40° C.;

[1080] UV wave length: 254 nm;

[1081] Flow rate: 1 mL/min;

[1082] Retention time:

[1083] (R)-1-benzyloxy-2-propanol: 8.1 min (89.5%);

[1084] (S)-1-benzyloxy-2-propanol: 9.2 min (10.5%).

[1085] The absolute structure was determined as R-form by comparing thespecific rotation with the known specific rotation disclosed in thefollowing reference.

[1086] Actual measurement value: [C]²⁶ _(D)=−11.8 (c=1.026, CHCl₃);

[1087] Literature data of S-form: [α]²⁴ _(D)=+13.2 (c=1, CHCl₃);

[1088] [α]_(D) reference: Naemura, K.; Asada, M.; Hirose, K.; Tobe, Y.,Tetrahedron:Asymmetry, 1995, 6, pp. 1873-1876.

Example 15

[1089] Asymmetric Hydrogenation of 2-methoxyacetophenone

[1090] Complex (R,R)-1 (1.5 mg, 1.25 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing 2-methoxyacetophene (376 mg, 2.5 mmol; mfd. by Aldrich), asolution of potassium tert-butoxide in 2-methyl-2-propanol (1.0 Msolution, 20 μL, 20 μmol; mfd. by Aldrich) and 2-propanol (2.5 mL) withvigorous stirring under a hydrogen atmosphere at 8 atm at 25° C. for 16hours.

[1091] After the reaction was completed, the thus obtained solution wasconcentrated under reduced pressure and compounds derived from thecomplex were removed by a silica gel chromatography treatment (silicagel 5 g; solvent: diethyl ether) to give (R)-1-phenyl-2-methoxyethanol(95% ee, 350 mg, 2.30 mmol, yield 92%) as a light yellow oil.

[1092] 1H-NMR (400 MHz, CDCl₃) δ 2.79 (s, 1H), 3.41-3.53 (m, 4H), 3.55(dd, 1H, J=9.6, 2.8), 4.89 (dd, 1H, J=8.8, 2.8), 7.29-7.40 (m, 5H).

[1093] The enantiomer excess was determined by means of GC analysis.

[1094] Column: Chirasil-DEX CB (inner diameter (df) 0.25 mm; size 0.32mm×25 mm; mfd. by CHROMPAK);

[1095] Column temperature: 120° C.;

[1096] Temperature of injection and detection: 200° C.;

[1097] Helium pressure: 44 kPa;

[1098] Retention time:

[1099] (S)-1-phenyl-2-methoxyethanol: 19.5 min (2.6%);

[1100] (R)-1-phenyl-2-methoxyethanol: 19.8 min (97.4%).

[1101] The absolute structure was determined by comparing the specificrotation with the known specific rotation disclosed in the followingreference.

[1102] Actual measurement value: [α]²⁷ _(D)=−38.4 (c=2.165, acetone);

[1103] Literature data of R-form (76% ee): [α]_(D)=−34.4 (c=2, acetone);

[1104] [α]_(D) reference: Ferraboschi, P.; Grisenti, P.; Manzocchi, A.;Santaniello, E., Tetrahedron, 1994, 50, pp. 10539-10548.

Example 16

[1105] Asymmetric Hydrogenation of Phenoxyacetone

[1106] Complex (R,R)-1 (1.5 mg, 1.25 mmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing phenoxyacetone (376 mg, 2.5 mmol; mfd. by TOKYO KASEI), a solutionof potassium tert-butoxide in 2-methyl-2-propanol (1.0 M solution, 20μL, 20 μmol; mfd. by Aldrich) and 2-propanol (2.5 mL) with vigorousstirring under a hydrogen atmosphere at 8 atm at 25° C. for 1 hour.

[1107] After the reaction was completed, the thus obtained solution wasconcentrated under reduced pressure and compounds derived from thecomplex were removed by a silica gel chromatography treatment (silicagel 15 g; solvent: diethyl ether) to give 1-phenoxy-2-propanol (80% ee,358 mg, 2.33 mmol, yield 93%) as a colorless oil.

[1108]¹H-NMR (270 MHz, CDCl₃) δ 1.29 (d, 3H, J=6.5), 2.36 (s, 1H), 3.79(dd, 1H, J=7.8, 9.2), 3.95 (dd, 1H, J=9.5, 3.0), 4.15-4.26 (m, 1H),6.89-7.00 (m, 3H), 7.24-7.33 (m, 2H).

[1109] The enantiomer excess was determined by means of GC analysis.

[1110] Column: Chirasil-DEX CB (inner diameter (df) 0.25 mm; size 0.32mm×25 mm; mfd. by CHROMPAK);

[1111] Column temperature: 100° C.;

[1112] Temperature of injection and detection: 200° C.;

[1113] Helium pressure: 44 kPa;

[1114] Retention time:

[1115] (S)-1-phenoxy-2-propanol: 52.9 min (90.0%);

[1116] (R)-1-phenoxy-2-propanol: 58.3 min (10.0%).

[1117] The absolute structure was determined as S-form by comparing thespecific rotation with the known specific rotation disclosed in thefollowing reference.

[1118] Actual measurement value : [α]²⁷ _(D)=−3.05 (c=3.04, C₂H₅OH);Literature data of S-form (>99% ee): [α]²⁰ _(D)=−2.7 (c=1.80, C₂H₅OH);

[1119] [α]_(D) reference: Waagen, V.; Partali, V.; Hollingsaeter, I.;Huang, M. S. S.; Anthonsen, T., Acta Chemica Scandinavica, 1994, 48, pp.506-510.

Example 17

[1120] Asymmetric Hydrogenation of2-(tert-butyldiphenylsilyl)oxyacetophenone (Intermediate 10)

[1121] Complex (R,R)-1 (1.5 mg, 1.25 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing Intermediate 10 (936 mg, 2.5 mmol), a solution of potassiumtert-butoxide in 2-methyl-2-propanol (1.0 M solution, 25 μL, 25 μmol;mfd. by Aldrich) and 2-propanol (2.5 mL) with vigorous stirring under ahydrogen atmosphere at 8 atm at 25° C. for 13 hours.

[1122] After the reaction was completed, an oil obtained by aconcentrating treatment under reduced pressure was subjected to a silicagel chromatography treatment (silica gel 50 g; solvent: hexane/diethylether=4/1) to give as the first fraction2-(tert-butyldiphenylsilyl)oxy-1-phenylethanol (746 mg, yield 79%) as acolorless oil; ¹H-NMR (400 MHz, CDCl₃) δ 1.08 (s, 9H), 3.00 (s, 1H),3.66 (dd, 1H, J=10.4, 8.4), 3.79 (dd, 1H, J=10.4, 3.6), 4.79-4.82 (m,1H), 7.25-7.44 (m, 11H), 7.60-7.66(m, 4H); and as the second fraction1-(tert-butyldiphenylsilyl)oxy-1-phenyletanol (107 mg, yield 11%) as acolorless oil: ¹H-NMR(400 MHz, CDCl₃) δ 1.06 (s, 9H), 3.56-3.59 (m, 1H),3.63-3.66 (m, 1H), 4.79 (dd, 1H, J=6.8, 4.4), 7.23-7.45 (m, 13H),7.68-7.70 (m, 2H).

[1123] The enantiomer excess and absolute structure were determined forthe diol form obtained by removing the silyl group as a protecting groupas described in Example 18.

Example 18

[1124] Synthesis of (R)-1-phenyl-1,2-ethanediol

[1125] Complex (R,R)-1 (1.5 mg, 1.25 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing Intermediate 10 (936 mg, 2.5 mmol), a solution of potassiumtert-butoxide in 2-methyl-2-propanol (1.0 M solution, 25 μL, 25 μmol;mfd. by Aldrich) and 2-propanol (2.5 mL) with vigorous stirring under ahydrogen atmosphere at 8 atm at 25° C. for 14 hours.

[1126] After the reaction was completed, the thus obtained solution wasput into a 20 mL recovery flask and concentrated under reduced pressure.THF (5 mL) and a solution of tetra-n-butylammonium fluoride in THF (1.0M solution, 3.75 mL, 3.75 mmol; mfd. by Aldrich) were added under aargon stream, and the resulting mixture was stirred at 25° C. for 8hours. The mixture was concentrated under reduced pressure and thensubjected to a silica gel chromatography treatment (silica gel 50 g;solvent: hexane/ethyl acetate=2/3) to give as the second fraction(R)-1-phenyl-1,2-ethanediol (97% ee, 320 mg, 2.32 mmol, yield 93%) as ayellow solid.

[1127]¹H-NMR (270 MHz, CDCl₃) δ 2.10 (br, 1H), 2.55 (br, 1H), 3.63-3.79(m, 2H), 4.83 (dd, 1H, J=7.9, 3.3), 7.23-7.40 (m, 5H).

[1128] The enantiomer excess was determined by means of HPLC analysis.

[1129] Chiral Column: CHIRALCEL OB (4.6 mm ID×250 mm; mfd. by Daicel);

[1130] Mobile phase: hexane/2-propanol (9/1);

[1131] Column temperature: 40° C.;

[1132] UV wave length: 254 nm;

[1133] Flow rate: 0.5 mL/min;

[1134] Retention time:

[1135] (R)-1-phenyl-1,2-ethanediol: 12.3 min (98.7%);

[1136] (S)-1-phenyl-1,2-ethanediol: 14.6 min (1.3%).

[1137] The absolute structure was determined as R-form by comparing thespecific rotation with the known specific rotation disclosed in thefollowing reference.

[1138] Actual measurement value: [a]²⁴ _(D)=−38.4(c=1.12, C₂H₅OH);

[1139] Literature data of S-form (99% ee): [α]²⁵ _(D)=+38.91(c=30.61,C₂H₅OH);

[1140] [α]_(D) reference: Cho, B. T.; Chun, Y. S., J.Org.Chem., 1998,63, pp. 5280-5282.

Example 19

[1141] Asymmetric Hydrogenation of 1,1-dimethoxy-2-propanone

[1142] Complex (R,R)-1 (1.5 mg, 1.25 [mol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing 1,1-dimethoxy-2-propanone (595 mg, 5.0 mmol; mfd. by Aldrich), asolution of potassium tert-butoxide in 2-methyl-2-propanol (1.0 Msolution, 40 μL, 40 μmol; mfd. by Aldrich) and 2-propanol (5 mL) withvigorous stirring under a hydrogen atmosphere at 8 atm at 25° C. for 8hours.

[1143] After the reaction was completed, GC analysis of the thusobtained solution showed that the product obtained was(S)-1,1-dimethoxy-2-propanol (yield 99%, enantiomer excess 98%).

[1144] GC

[1145] Column: Chirasil-DEX CB;

[1146] Column temperature: 60° C.;

[1147] Temperature of injection and detection: 250° C.;

[1148] Helium pressure: 44 kPa;

[1149] Retention time:

[1150] 1,1-dimethoxy-2-propanone: 10.0 min (0.3%);

[1151] (R)-1,1-dimethoxy-2-propanol: 22.8 min (0.6%);

[1152] (S)-1,1-dimethoxy-2-propanol: 23.6 min (99.1%).

[1153] The absolute structure was determined as S-form by comparing thespecific rotation with the known specific rotation disclosed in thefollowing reference.

[1154] Actual measurement value: [α]265D=−180.0(c=0.16, CH₃OH);

[1155] Literature data of S-form (87% ee): [α]²⁵ _(D)=−12.15(c=3.21,CH₃OH);

[1156] [a]_(D) reference: Cho, B. T.; Chun, Y. S.,Tetrahedron:Asymmetry, 1994, 5, pp. 1147-1150.

Example 20

[1157] Asymmetric Hydrogenation of 2,2-diethoxyacetophenone

[1158] Complex (R,R)-1 (3.1 mg, 2.5 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing 2,2-diethoxyacetophenone (517 mg, 2.5 mmol; mfd. by TOKYO KASEI),a solution of potassium tert-butoxide in 2-methyl-2-propanol (1.0 Msolution, 50 μL, 50 μmol; mfd. by Aldrich) and 2-propanol (2.5 mL) withvigorous stirring under a hydrogen atmosphere at 8 atm at 25° C. for 8hours.

[1159] After the reaction was completed, GC analysis of the thusobtained solution showed that the product obtained was(S)-2,2-diethoxy-1-phenylethanol (yield 100%, enantiomer excess 37%).

[1160] GC

[1161] Column: Chirasil-DEX CB;

[1162] Column temperature: 120° C.;

[1163] Temperature of injection and detection: 250° C.;

[1164] Helium pressure: 44 kPa;

[1165] Retention time:

[1166] 2,2-diethoxyacetophene: 22.7 min (0%);

[1167] (S)-2,2-diethoxy-1-phenylethanol: 45.5 min (31.3%);

[1168] (R)-1,1-diethoxy-2-propanol: 47.9 min (68.7%).

[1169] The absolute structure was determined as S-form by comparing thespecific rotation of the hydrogenated product per se (Actual measurementvalue: [α]²⁷ _(D)=−6.95 (c=1.995, CHCl₃)) with the specific rotationdisclosed in the reference (Cho, B. T.; Chun, Y. S.,Tetrahedron:Asymmetry, 1994, 5, pp. 1147-1150).

Example 21

[1170] Asymmetric Hydrogenation of2-[bisbenzylamino]-1-[3-[(methylsulfonyl)benzylamino]phenyl]ethanone(Intermediate 4)

[1171] Complex (S,S)-1 (2.6 mg, 2.12 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing Intermediate 4 (1.07 g, 2.15 mmol), a solution of potassiumtert-butoxide in 2-methyl-2-propanol (1.0 M solution, 172 μL, 172 μmol;mfd. by Aldrich) and 2-propanol (4.3 mL) with vigorous stirring under ahydrogen atmosphere at 8 atm, at 30° C. for 14 hours.

[1172] After the reaction was completed, the thus obtained solution wasconcentrated under reduced pressure and compounds derived from thecomplex were removed by a silica gel chromatography treatment (silicagel 15 g; solvent: diethyl ether) to give(S)-2-[bisbenzylamino]-1-[3-[(methylsulfonyl)benzylamino]phenyl]ethanol(88% ee, 1.05 g, yield 97%) as a colorless oil.

[1173]¹H-NMR (300 MHz, CDCl₃) δ 2.47 (dd, 1H, J=12.9, 9.9), 2.57 (dd,1H, J=12.9, 3.4), 2.86 (s, 3H), 3.46 (d, 2H, J=13.5), 3.89 (d, 2H,J=13.5), 4.62 (dd, 1H, J=9.9, 3.4), 4.78 (s, 2H), 7.07-7.39 (m, 19H).

[1174] The enantiomer excess was determined by means of HPLC analysis.

[1175] Chiral Column: CHIRALCEL OJ-R (4.6 mm ID×150 mm; mfd. by Daicel);

[1176] Mobile phase: 0.5 M NaClO₄-HClO₄(pH=2.0)/acetonitrile (74/26) 1pump;

[1177] Column temperature: 40° C.;

[1178] UV wave length: 233 nm;

[1179] Flow rate: 0.5 mL/min;

[1180] Retention time:

[1181] (R)-form: 56.1 min (5.8%);

[1182] (S)-form: 61.9 min (94.2%);

[1183] R_(f)=0.51 (1/1 n-hexane/ethyl acetate).

Example 22

[1184] Asymmetric Hydrogenation of1-[4-chloro-3-[(methylsulfonyl)benzylamino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanoneMonohydrochloride (Intermediate 5 Monohydrochloride Salt) (s/c=10,000)

[1185] Complex (R,R)-1 (1.6 mg, 1.3 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing Intermediate 5 monohydrochloride salt (8.63 g, 12.5 mmol),potassium tert-butoxide (1.71 g, 14.75 mmol; mfd. by KANTO KAGAKU) and amixed solvent of 2-propanol (25 mL) and DMF (6.5 mL) with vigorousstirring under a hydrogen atmosphere at 8 atm at 30° C. for 7 hours.

[1186] After the reaction was completed, the thus obtained solution wasconcentrated under reduced pressure, diluted with ethyl acetate andwashed with saturated brine. The solvent was then distilled off, andcompounds derived from the complex were removed from the residue by asilica gel chromatography treatment (silica gel 25 g; solvent: ethylacetate) to give(R)-1-[4-chloro-3-[(methylsulfonyl)benzylamino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanol(91% ee, 7.53 g, yield 92%) as a colorless amorphous solid.

[1187]¹H-NMR (300 MHz, CDCl₃) δ 2.91 (m, 2H), 3.16 (s, 3H), 3.75 (m,2H), 4.02 (m, 2H), 4.61-4.82 (m, 4H), 5.23 (m, 1H), 6.72 (dd, 1H, J=8.5,2.2), 6.92 (d, 1H, J=2.2), 7.07-7.44 (m, 16H), 7.93-8.01 (m, 2H), 11.07(s, 1H).

[1188] The enantiomer excess was determined by means of HPLC analysis.

[1189] Chiral Column: CHIRALCEL OJ-R (4.6 mm ID×150 mm; mfd. by Daicel);

[1190] Mobile phase: 0.5 M NaClO₄ aq./acetonitrile (30/70) 1 pump;

[1191] Column temperature: 40° C.;

[1192] UV wave length: 233 nm;

[1193] Flow rate: 0.5 mL/min;

[1194] Retention time:

[1195] (R)-form: 27.0 min (89.6%);

[1196] (S)-form: 20.9 min (4.2%);

[1197] R_(f)=0.64 (1/1 n-hexane/ethyl acetate).

Example 23

[1198] Asymmetric Hydrogenation of1-[3-[(methylsulfonyl)benzylamino]-phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanoneMonohydrochloride (Intermediate 6 Monohydrochloride Salt) (S-Form)

[1199] Complex (S,S)-4 (1.49 mg, 1.25 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing Intermediate 6 monohydrochloride salt (1.64 g, 2.5 mmol),potassium tert-butoxide (341.3 mg, 2.95 mmol; mfd. by KANTO KAGAKU) anda mixed solvent of 2-propanol (12.6 mL) and DMA (12.6 mL) with vigorousstirring under hydrogen atmosphere at 8 atm at 23° C. for 45 minutes.

[1200] After the reaction was completed, the thus obtained solution wasconcentrated under reduced pressure, diluted with ethyl acetate andwashed with saturated brine. The solvent was then distilled off, andcompounds derived from the complex were removed from the residue by asilica gel chromatography treatment (silica gel 25 g; solvent: ethylacetate) to give(S)-1-[3-[(methylsulfonyl)benzylamino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanol(96% ee, 1.5 g, yield 97%) as a colorless amorphous solid.

[1201]¹H-NMR (500 MHz, CDCl₃) δ 2.60 (dd, 1H, J=13.2, 10.3), 2.83 (dd,1H, J=13.2, 2.9), 2.89 (s, 3H), 2.97-3.04 (m, 1H), 3.09-3.15 (m, 1H),3.70 (d, 2H, J=13.7), 3.96 (d, 2H, J=13.7), 4.13 (m, 2H), 4.66 (dd, 1H,J=10.3, 3.4), 4.77 (d, 1H, J=14.7), 4.81 (d, 1H, J=14.7), 6.84 (dd, 1H,J=8.3, 2.0), 6.92 (d, 1H, J=2.0), 7.10-7.41 (m, 17H), 7.93 (d, 2H,J=8.8), 7.97 (d, 1H, J=7.8), 8.14 (s, 1H).

[1202] The enantiomer excess was determined by means of HPLC analysis.

[1203] Chiral Column: CHIRALCEL OJ-R (4.6 mm ID×150 mm; mfd. by Daicel);

[1204] Mobile phase: 0.5 M NaClO₄ aq./acetonitrile (30/70) 1 pump;

[1205] Column temperature: 40° C.;

[1206] UV wave length: 233 nm;

[1207] Flow rate: 0.5 mL/min;

[1208] Retention time:

[1209] (S)-form: 18.6 min (97.7%);

[1210] (R)-form: 26.3 min (2.2%);

[1211] R_(f)=0.27 (1/1 n-hexane/ethyl acetate)

Example 24

[1212](R)-2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[3-(methylsulfonylamino)phenyl]ethanolMonohydrochloride

[1213] Step 1. Asymmetric Hydrogenation of1-[3-[(methylsulfonyl)benzylamino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanoneMonohydrochloride (Intermediate 6 Monohydrochloride Salt) (R-Form)

[1214] Complex (R,R)-1 (1.6 mg, 1.25 μmol) was measured into a 100 mLglass autoclave equipped with a teflon-coated stirrer. An asymmetrichydrogenation according to the procedure of Example 5 was carried outusing Intermediate 6 monohydrochloride salt (8.18 g, 12.5 mmol),potassium tert-butoxide (1.71 g, 14.75 mmol; mfd. by KANTO KAGAKU) and amixed solvent of 2-propanol (25 mL) and DMA (6.5 mL) with vigorousstirring under a hydrogen atmosphere at 8 atm at 23° C. for 4 hours.

[1215] After the reaction was completed, the thus obtained solution wasconcentrated under reduced pressure, diluted with ethyl acetate andwashed with saturated brine. The solvent was then distilled off, andcompounds derived from the complex was removed from the residue by asilica gel chromatography treatment (silica gel 25 g; solvent: ethylacetate) to give(R)-1-[3-[(methylsulfonyl)benzylamino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanol(91% ee, 8.65 g, yield 99%) as a colorless amorphous solid.

[1216] The enantiomer excess was determined by means of HPLC analysis.

[1217] Chiral Column: CHIRALCEL OJ-R (4.6 mm ID×150 mm; mfd. by Daicel);

[1218] Mobile phase: 0.5 M NaClO₄ aq./acetonitrile (30/70) 1 pump;

[1219] Column temperature: 40° C.;

[1220] UV wave length: 233 nm;

[1221] Flow rate: 0.5 mL/min;

[1222] Retention time:

[1223] (S)-form: 18.2 min (3.6%);

[1224] (R)-form: 25.0 min (94.8%);

[1225] R_(f)=0.27 (1/1 n-hexane/ethyl acetate).

[1226] Step. 2 Synthesis of(R)-2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[3-(methylsulfonylamino)phenyl]ethanolMonohydrochloride

[1227](R)-1-[3-[(Methylsulfonyl)benzylamino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanol(10 g; obtained in the above step) was dissolved in a mixed solvent oftetrahydrofuran (100 mL) and methanol (100 mL), and a palladiumhydroxide/carbon catalyst (1 g; mfd. by Nacalai Tesque) was added undera nitrogen atmosphere. The resulting mixture was subjected to ahydrogenolysis treatment with stirring under a hydrogen atmosphere atatmospheric pressure at room temperature through a night. The catalystwas filtered off, and the solvent was distilled off under reducedpressure. The crystal collected by suction filtration was washed with amixed solvent of tetrahydrofuran and methanol (1:1).

[1228] The crystal was then dissolved in methanol (150 mL). After 0.1 Nhydrochloric acid/ethanol was added to form hydrochloride salt, thedeposited crystal was collected by suction filtration. The crystal wasdried by heating (40° C.) under reduced pressure to give a hydrochloridesalt of the title compound (7.50 g) as a white crystal. R_(f)=0.3 (10/1chloroform/methanol); MH⁺=441.

[1229] The thus obtained compound was shown to be identical to the titlecompound prepared according to the known method (WO 97/25311) by thefact that they had the same retention time in HPLC measurements. Thiscompound is described in WO 97/25311 as being very useful for treatingand preventing diabetes, obesity, hyperlipidemia and the like.

Example 25

[1230] Trans-RuCl₂[(R)-(2,6-dimethylanisol-4-yl)binap][(R)-damen]Complex (Designated as Complex (R,R)-25); Abbreviated Name:Trans-RuCl₂](R)-dmanylbinap][(R)-damen]; Formula (23):

[1231] Step 1. Synthesis of(R)-2,2′-bis[bis(3,5-dimethyl-4-methoxyphenyl)phosphino]-1,1′-binaphthyl(Intermediate 11) (Process A and Process B); Abbreviated Name:(R)-Dmanyl-BINAP); Formula (24):

[1232] (Process A)

[1233] 5% Palladium/activated carbon (163 mg; mfd. by Aldrich) and1,4-diazabicyclo[2.2.2]octane (415 mg, 3.53 mmol; mfd. by Aldrich) wereadded to a 50 mL glass Schlenk tube equipped with a teflon-coatedstirrer which had been previously dried by heating under reducedpressure, and the tube was then sealed tightly. The reactor was degassedby applying the pressure-reducing/argon-introducing procedure fivetimes. Under an argon atmosphere, dried DMF (7.5 mL) which had beenpreviously degassed by means of vacuum freezing was added, followed byaddition of bis(3,5-dimethyl-4-methoxy-phenyl)chlorophosphine (0.9 mL,ca. 3.5 mmol; synthesized by the method described in the literature:Tetrahedron:Asymmetry, Vol. 10, pp. 3341-3352 (1999)) with stirring. Theprocedure of reducing pressure followed by replacing the atmosphere withhydrogen at atmospheric pressure was repeated seven times. The reactionliquid was stirred under a hydrogen atmosphere at 1 atm at 100° C. for 2hours. After allowed to cool down to room temperature, the reactionliquid was filtered through dried Celite under an argon atmosphere. Thefiltrate was collected in a 50 mL Schlenk tube which had been previouslydried by heating under reduced pressure, and then concentrated underreduced pressure. To the residue, (R)-(−)-1,1′-bi-2-naphtholbis(trifluoromethanesulfonate) (802 mg, 1.41 mmol; mfd. by FLUKA),[1,2-bis(diphenylphosphino)ethane]dichloronickel(II) (75 mg, 0.14 mmol;mfd. by Aldrich) and a solution of 1,4-diazabicyclo-[2.2.2]octane (668mg, 5.84 mmol; mfd. by Aldrich) in dried DMF (7.5 mL) previouslydegassed by means of vacuum freezing were added under an argonatmosphere. The resulting mixture was stirred at 100° C. for 106 hours.After cooled down to room temperature, the mixture was filtered throughdried Celite under an argon atmosphere and the filtrate was concentratedunder reduced pressure. The residue was extracted with ethyl acetate (22mL) and purified water (11 mL). The organic layer was washedsequentially with 1 N hydrochloric acid (11 mL) and aqueous saturatedammonium chloride (11 mL), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified threetimes by silica gel column chromatography (20 mL, neutral sphericalshape; 100/0-40/1 n-hexane/ethyl acetate) to give Intermediate 11 (334.7mg). MS(EI)m/z 854[M]⁺.

[1234] Process B

[1235] To a 50 mL glass Schlenk tube equipped with a teflon-coatedstirrer which had been previously dried by heating under reducedpressure, 5% palladium/activated carbon (0.2 g; mfd. by Aldrich),1,4-diazabicyclo[2.2.2]octane (1.46 g, 12.75 mmol; mfd. by Aldrich),(R)-(−)-1,1′-bi-2-naphthol bis(trifluoromethanesulfonate) (1.10 g, 1.92mmol; mfd. by FLUKA) and[1,2-bis(diphenylphosphino)ethane]dichloronickel(II) (110 mg, 0-0.2mmol; mfd. by Aldrich) were added, and the tube was then sealed tightly.The reactor was degassed by applying thepressure-reducing/argon-introducing procedure five times. Under an argonatmosphere, dried DMA (11 mL) which had been previously degassed bymeans of vacuum freezing was added, followed by addition ofbis(3,5-dimethyl-4-methoxyphenyl)chlorophosphine (1.25 mL, ca.4.8 mmol;synthesized by the method described in the literature:Tetrahedron:Asymmetry, Vol. 10, pp. 3341-3352 (1999)) with stirring. Theprocedure of reducing pressure followed by replacing the atmosphere withhydrogen at atmospheric pressure was repeated seven times. The reactionliquid was stirred under a hydrogen atmosphere at 1 atm at 100° C. for110 hours. After allowed to cool down to room temperature, the reactionliquid was filtered through dried Celite under an argon atmosphere, andthe filtrate was concentrated under reduced pressure. The residue wasthen subjected to extracting treatment, washing treatment and purifyingtreatment by silica gel column chromatography according to Process A togive Intermediate 11 (492.5 mg).

[1236] Step 2. Synthesis of Complex (R,R)-25

[1237] According to the procedures of Examples 1 and 4, the titleComplex (R,R)-25 (56.1 mg, yellow solid) was synthesized from[RuCl₂(benzene)]₂ (25.5 mg, 0.05 mmol), Intermediate 11 (85.5 mg, 0.10mmol; obtained in Step 1) and (R)-DAMEN (31.5 mg, 0.11 mmol; synthesizedby the method described in the literature: Burrows, C. J. et al.,Tetrahedron Letters, 34(12), pp. 1905-1908 (1993)). MS(FAB)m/z 1404[MH]⁺.

Example 26

[1238] Asymmetric Hydrogenation of1-[3-[(methylsulfonyl)benzylamino]-phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanoneMonohydrochloride (Intermediate 6 Monohydrochloride Salt) (R-Form)

[1239] Complex (R,R)-25 (1.76 mg, 1.25 μmol; synthesized in Example 25)was measured into a 100 mL glass autoclave equipped with a teflon-coatedstirrer. An asymmetric hydrogenation according to the procedure ofExample 5 was carried out using Intermediate 6 monohydrochloride salt(1.64 g, 2.5 mmol), potassium tert-butoxide (350 mg, 3 mmol; mfd. byKANTO KAGAKU) and a mixed solvent of 2-propanol (5 mL) and DMA (1.3 mL)under a hydrogen atmosphere at 8 atm at 23° C. for 4 hours with vigorousstirring. After the reaction was completed, the thus obtained solutionwas concentrated under reduced pressure, diluted with ethyl acetate andwashed with saturated brine. The solvent was then distilled off, andcompounds derived from the complex were removed from the residue by asilica gel chromatography treatment (silica gel 10 g; solvent: ethylacetate) to give(R)-1-[3-[(methylsulfonyl)benzylamino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanol(96% ee, 1.53 g, yield 99%) as a colorless amorphous solid. Theenantiomer excess was determined by means of HPLC analysis.

[1240] Chiral Column: CHIRALCEL OJ-R (4.6 mm ID×150 mm; mfd. by Daicel);

[1241] Mobile phase: 0.5 M NaClO₄ aq./acetonitrile (30/70) 1 pump;

[1242] Column temperature: 40° C.;

[1243] UV wave length: 233 nm;

[1244] Flow rate: 0.5 mL/min;

[1245] Retention time:

[1246] (S)-form: 18.2 min (1.9%);

[1247] (R)-form: 25.0 min (97.9%);

[1248] R_(f)=0.27 (1/1 n-hexane/ethyl acetate).

[1249] According to the hydrogenolysis procedure and hydrochloridesalt-forming procedure in Step 2 of Example 24, the above compound canbe converted into(R)-2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[3-(methylsulfonylamino)phenyl]ethanolmonohydrochloride which is described in WO 97/25311 as being very usefulfor treating and preventing diabetes, obesity, hyperlipidemia and thelike.

Example 27

[1250] Trans-RuCl₂[(R)-xyl-6,6′-dimethylbinap] (R)-damen] Complex(Designated as Complex (R,R)-27); Abbreviated Name:Trans-RuCl₂[(R)-xyl-6mebinap][(R)-damen]; Formula (25):

[1251] Step 1. Synthesis of (R)-6,6′-dimethyl-1,1′-bi-2-naphtholBis(Trifluoromethanesulfonate) (Intermediate 12); Formula (26):

[1252] Under an argon atmosphere, (R)-6,6′-dimethyl-1,1′-bi-2-naphthol(9.432 g, 30 mmol; mfd. by KANKYO KAGAKU CENTER) was placed in a 300 mLrecovery flask equipped with a teflon-coated stirrer, and then dissolvedwith dehydrated dichloromethane (60 mL). Under ice-cooling and stirring,dehydrated pyridine (7.2 mL, 90 mmol) was added, followed bytrifluoromethanesulfonic anhydride (20 g, 70 mmol; mfd. by TOKYO KASEI).The resulting mixture was stirred with ice-cooling for 30 minutes, andthen further stirred for 17 hours while its temperature was allowed towarm to room temperature. n-Hexane (60 mL) was added with vigorousstirring. The precipitate generated was removed by filtration withsilica gel pad (50 g) and the silica gel pad was washed with a mixedsolvent of n-hexane/dichloromethane (1/1; 200 mL). The solvent wasdistilled off from the combined filtrates under reduced pressure. Theresidue was dried under reduced pressure with vacuum pump (ca. 0.5 mmHg)for 3 hours to give Intermediate 12 (17.18 g; colorless amorphoussolid). MS(EI)m/z 578[M]⁺.

[1253] Step 2. Synthesis of(R)-(+)-2,2′-bis[bis(3,5-dimethylphenyl)phosphino]-6,6′-dimethyl-1,1′-binaphthyl(Intermediate 13; Abbreviated Name: (R)-Xyl-6MeBINAP); Formula (27)

[1254] To a 50 mL glass Schlenk tube equipped with a teflon-coatedstirrer which had been previously dried by heating under reducedpressure, 5% palladium/activated carbon (0.2 g; mfd. by Aldrich),1,4-diazabicyclo[2.2.2]octane (1.49 g, 13 mmol; mfd. by Aldrich),Intermediate 12 (1.14 g, 1.96 mmol) and[1,2-bis(diphenylphosphino)ethane]dichloronickel(II) (0.1 g, 0.2 mmol;mfd. by Aldrich) were added, and the tube was then sealed tightly. Thereactor was degassed by applying the pressure-reducing/argon-introducingprocedure five times. Under an argon atmosphere, dried DMF (10 mL) whichhad been previously degassed by means of vacuum freezing was added,followed by addition of bis(3,5-dimethylphenyl)chlorophosphine (1.14 mL,ca.4.9 mmol; mfd. by Digital Specialty Chemicals, Inc.) with stirring.The procedure of reducing pressure followed by replacing the atmospherewith hydrogen at atmospheric pressure was repeated seven times. Thereaction liquid was stirred under a hydrogen atmosphere at 1 atm at 100°C. for 110 hours. After allowed to cool down to room temperature, thereaction liquid was filtered through dried Celite under an argonatmosphere. The filtrate was collected in a 50 mL Schlenk tube which hadbeen previously dried by heating under reduced pressure, and thenconcentrated under reduced pressure. The residue was extracted withethyl acetate (30 mL) and purified water (15 mL). The organic layer waswashed sequentially with 1 N hydrochloric acid (15 mL) and aqueoussaturated ammonium chloride (15 mL), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified three times by silica gel column chromatography (20 mL,neutral; 100/0 to 50/1 n-hexane/ethyl acetate) to give Intermediate 13(448.6 mg). MS(EI)m/z 762[M]⁺.

[1255] Step 3. Synthesis of Complex (R,R)-27

[1256] According to the procedures of Examples 1 and 4, the titleComplex (R,R)-27 (52.0 mg, yellow solid) was synthesized from[RuCl₂(benzene)]₂ (25.5 mg, 0.05 mmol), Intermediate 13 (76.3 mg, 0.10mmol) and (R)-DAMEN (31.5 mg, 0.11 mmol; synthesized by the methoddescribed in the literature: Burrows, C. J., et al., TetrahedronLetters, 34(12), pp. 1905-1908 (1993)). MS(FAB)m/z 1312[MH]⁺.

Example 28

[1257] Asymmetric Hydrogenation of1-[3-[(methylsulfonyl)benzylamino]-phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanoneMonohydrochloride (Intermediate 6 Monohydrochloride Salt) (R-Form)

[1258] Complex (R,R)-27 (1.64 mg, 1-0.25 μmol; synthesized in Example27) was measured into a 100 mL glass autoclave equipped with ateflon-coated stirrer. An asymmetric hydrogenation according to theprocedure of Example 5 was carried out using Intermediate 6monohydrochloride salt (1.64 g, 2.5 mmol), potassium tert-butoxide (350mg, 3 mmol; mfd. by KANTO KAGAKU) and a mixed solvent of 2-propanol (5mL) and DMA (1.3 mL) under a hydrogen atmosphere at 8 atm at 25° C. for4 hours with vigorous stirring. After the reaction was completed, thethus obtained solution was concentrated under reduced pressure, dilutedwith ethyl acetate and washed with saturated brine. The solvent was thendistilled off, and compounds derived from the complex were removed fromthe residue by a silica gel chromatography treatment (silica gel 10 g;solvent: ethyl acetate) to give(R)-1-[3-[(methylsulfonyl)benzylamino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanol(96% ee, 1.53 g, yield 99%) as a colorless amorphous solid. Theenantiomer excess was determined by means of HPLC analysis.

[1259] Chiral Column: CHIRALCEL OJ-R (4.6 mm ID×150 mm; mfd. by Daicel);

[1260] Mobile phase: 0.5 M NaClO₄ aq./acetonitrile (30/70) 1 pump;

[1261] Column temperature: 40° C.;

[1262] UV wave length: 233 nm;

[1263] Flow rate: 0.5 mL/min;

[1264] Retention time:

[1265] (S)-form: 18.2 min (1.9%);

[1266] (R)-form: 25.0 min (97.9%);

[1267] R_(f)=0.27 (1/1 n-hexane/ethyl acetate).

[1268] According to the hydrogenolysis procedure and hydrochloridesalt-forming procedure in Step 2 of Example 24, the above compound canbe converted into(R)-2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[3-(methylsulfonylamino)phenyl]ethanolmonohydrochloride which is described in WO 97/25311 as being very usefulfor treating and preventing diabetes, obesity, hyperlipidemia and thelike.

Reference Example 1

[1269] 2-bromo-1-[3-[N,N-benzyl(methylsulfonyl)amino]phenyl]ethanone(Intermediate 1)

[1270] Step 1. Synthesis of1-[3-[N,N-benzyl(methylsulfonyl)amino]-phenyl]ethanone

[1271] 1-[3-[N-(methylsulfonyl)amino]phenyl]ethanone (90.68 g;synthesized by the method described in Larsen, A. A., J. Med. Chem., 9,pp. 88-97 (1966)) was dissolved in acetone (639.6 mL) at 23° C.,followed by addition of anhydrous potassium carbonate (66.0 g). Understirring, benzyl bromide (56.6 mL; mfd. by Wako Pure ChemicalIndustries) was added at a stretch. Sodium iodide (13.01 g; mfd. by WakoPure Chemical Industries) was added and the resulting mixture wasvigorously stirred under heating to reflux. After 2 hours, anhydrouspotassium carbonate (29.4 g) and sodium iodide (32 g) were further addedand stirring was continued. After 1 hour, anhydrous potassium carbonate(29.4 g) and sodium iodide (32 g) were further added and vigorousstirring was continued at the same temperature for 13.5 hours. Afterallowing to cool by itself to 43° C., purified water (1090 mL) was addedat a stretch and vigorously stirred. The resulting reaction liquid wasextracted with ethyl acetate (495 mL). The separated organic layer waswashed with saturated brine (495 mL) and dried over anhydrous magnesiumsulfate (90 g) for 0.5 hour. The desiccating agent was filtered off andthe solvent was then distilled off under reduced pressure.

[1272] The thus obtained crude product (139.42 g) was suspended in ethylacetate (343 mL), then n-hexane (445 mL) was added under heating toreflux. The crude product was completely dissolved by further addingethyl acetate (20 mL) under heating to reflux. This was recrystalizedunder ice-cooling and stirring to give1-[3-[N,N-benzyl(methylsulfonyl)amino]phenyl]ethanone (71.71 g).

[1273]¹H-NMR (300 MHz, CDCl₃) δ 2.55 (s, 3H), 2.97 (s, 3H), 4.88 (s,2H), 7.20-7.30 (m, 5H), 7.41 (m, 1H), 7.46 (dt, 1H, J=8.2, 1.9),7.81-7.86 (m, 2H);

[1274] R_(f)=0.44 (1/1 ethyl acetate/n-hexane).

[1275] Step 2. Synthesis of2-bromo-1-[3-[N,N-benzyl(methylsulfonyl)amino]phenyl]ethanone(Intermediate 1)

[1276] 1-[3-[N,N-benzyl(methylsulfonyl)amino]phenyl]ethanone (71.21 g;synthesized in Step 1 of Reference Example 1) was dissolved in methanol(3.94 L) and tetra-n-butylammonium tribromide (127 g; mfd. by Aldrich)was added at a stretch. After stirring at room temperature for 13 hours,a mixed solution of 47% hydrobromic acid (985 mL) and purified water(985 mL) was added at a stretch. The reaction mixture was stirred for 1hour while the internal temperature was maintained at from 35 to 40° C.Purified water (985 mL) was added, and the internal temperature wasgradually lowered to 30° C. with vigorous stirring over 3 hours. Thereaction mixture was further cooled to 5° C. and stirred for 2 hours.The precipitated crystal was collected by filtration and washed twicewith a mixed liquid (2.5 L) of methanol and water. The wet crystal wasdried at 50° C. under reduced pressure for 24 hours to give the titlecompound (Intermediate 1; 73.80 g).

[1277]¹H-NMR (300 MHz, CDCl₃) δ 2.98 (s, 3H), 4.36 (s, 2H), 4.89 (s,2H), 7.20-7.30 (m, 5H), 7.44 (t, 1H, J=8.0), 7.51 (dt, 1H, J=8.0, 1.7),7.84-7.89 (m, 2H);

[1278] R_(f)=0.46 (1/1 ethyl acetate/n-hexane).

Reference Example 2

[1279]2-bromo-1-[4-chloro-3-[N,N-benzyl(methylsulfonyl)amino]phenyl]-ethanone(Intermediate 2)

[1280] Step. 1 Synthesis of1-[4-chloro-3-[N,N-benzyl(methylsulfonyl)amino]phenyl]ethanone

[1281] 1-[4-chloro-3-[N-(methylsulfonyl)amino]phenyl]ethanone (90.68 g;synthesized by the method described in WO 97/25311) was dissolved in DMF(50 mL) at 23° C., and anhydrous potassium carbonate (31.7 g) was thenadded. Under stirring, benzyl bromide (21.6 g; mfd. by Wako PureChemical Industries) was added at a stretch, and the resulting mixturewas vigorously stirred at the same temperature for 2.5 days. Purifiedwater (200 mL) was added at a streach. The resulting mixture wasvigorously stirred and then extracted with ethyl acetate (200 mL) andn-heptane (50 mL). The separated organic layer was washed twice withpurified water (100 mL), washed with saturated brine (200 mL), and driedover anhydrous sodium sulfate. The desiccating agent was filtered offand the solvent was then distilled off under reduced pressure.

[1282] The thus obtained crude product was purified by silica gelchromatography (1.5 kg) to give the title compound (27.63 g) as a lightyellow oil from the fraction eluted with ethyl acetate/n-hexane (1/4 to3/7).

[1283]¹H-NMR (300 MHz, CDCl₃) δ 2.40 (s, 3H), 3.08 (s, 3H), 4.58 (br,1H), 5.09 (br, 1H), 7.22-7.32 (m, 5H), 7.53 (d, 1H, J=8.2), 7.56 (d, 1H,J=2.2), 7.82 (dd, 1H, J=8.2,2.2);

[1284] R_(f)=0.43 (1/1 ethyl acetate/n-hexane).

[1285] Step 2. Synthesis of2-bromo-1-[4-chloro-3-[N,N-benzyl(methanesulfonyl)amino]phenyl]ethanone(Intermediate 2)

[1286] 1-[4-Chloro-3-[N,N-benzyl(methylsulfonyl)amino]phenyl]ethanone(58.31 g; synthesized in Step 1 of Reference Example 2) was dissolved in1,4-dioxane (583.1 mL), and tetra-n-butylammonium tribromide (91.55 g;mfd. by TOKYO KASEI) was added at a stretch. After stirring at roomtemperature for 15 hours, the reaction liquid was concentrated underreduced pressure. The residue was purified twice by silica gelchromatography (1 kg) to give the title compound (Intermediate 2; 54.26g) from the fraction eluted with ethyl acetate/n-hexane (1/5 to 1/2).

[1287]¹H-NMR (300 MHz, CDCl₃) δ 3.09 (s, 3H), 4.21 (br-s, 2H), 4.60 (br,1H), 5.11 (br, 1H), 7.22-7.32 (m, 5H), 7.57 (d, 1H, J=8.5), 7.61 (d, 1H,J=2.2), 7.87 (dd, 1H, J=8.5, 2.2);

[1288] R_(f)=0.44 (1/1 ethyl acetate/n-hexane).

Reference Example 3

[1289] N,N-benzyl[2-(9H-carbazol-2-yloxy)ethyl]amine (Intermediate 3)

[1290] Benzaldehyde (93.8 g; mfd. by Wako Pure Chemical Industries) wasadded to a solution of N-[2-(9H-carbazol-2-yloxy)ethyl]amine (200 g;synthesized by the method described in JP-A-9-249623) in methanol (5 L),and the resulting mixture was stirred at room temperature for 1 hour.Platinum oxide (10.0 g; mfd. by Wako Pure Chemical Industries) was addedunder an argon atmosphere, and the resulting mixture was stirred under ahydrogen atmosphere at 1 atm for 3 hours. After the atmosphere in thereaction system is replaced with argon, benzaldehyde (18.8 g) wasfurther added. The reaction mixture was further stirred under a hydrogenatmosphere at 1 atm for 3 hours. The atmosphere in the reaction systemwas purged with argon, and the catalyst was then filtered off. Thesolvent was distilled off from the filtrate under reduced pressure. Theresidue was recrystalized from ethanol. The crystal collected byfiltration was dried under reduced pressure to give the title compound(Intermediate 3; 252.0 g) as a slightly yellowish crystal.

[1291] R_(f)=0.60 (10/1 chloroform/methanol); MH⁺=317;

[1292]¹H-NMR (300 MHz, DMSO-d₆; free-form) δ 2.30 (s, 1H), 2.91 (t, 2H,J=5.8), 3.79 (s, 2H), 4.11 (t, 2H, J=5.8), 6.77 (dd, 1H, J=8.5, 2.2),6.96 (d, 1H, J=2.2), 7.10 (m, 1H), 7.20-7.44 (m, 7H), 7.92-8.00 (m, 2H),11.09 (s, 1H).

Reference Example 4

[1293]2-[bisbenzylamino]-1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-ethanoneMonohydrochloride (Intermediate 4 Monohydrochloride Salt)

[1294] Dibenzylamine (42.4 g; mfd. by TOKYO KASEI) was dissolved in THF(400 mL). Under stirring, Intermediate 1 (40 g) was added at a stretchat room temperature. After stirring for 3 hours, the precipitateddibenzylamine hydrobromide was filtered off and the solvent wasdistilled off under reduced pressure. The residue was dissolved in THF(200 mL), and then converted into its hydrochloride salt by adding 36%hydrochloric acid (9.9 mL) with stirring. The precipitated hydrochloridesalt was collected by filtration, washed with THF (70 mL) and dried at40° C. under reduced pressure to give the first crystal. In addition,the filtrate was concentrated and redissolved in THF (60 mL). Theprecipitated hydrochloride salt was collected by filtration, washed withTHF (50 mL) and dried at 40° C. under reduced pressure to give thesecond crystal. The first crystal and the second crystal were combinedto give the title compound (Intermediate 4; 53.67 g).

[1295]¹H-NMR (300 MHz, DMSO-d₆; hydrochloride salt) δ 3.13 (s, 3H),4.25-4.60 (m, 4H), 4.85 (br, 2H), 4.93 (s, 2H), 7.16-7.72 (m, 18H), 7.81(s, 1H), 10.62 (br, 1H);

[1296] R_(f)=0.36 (1/2 ethyl acetate/n-hexane).

Reference Example 5

[1297]1-[4-chloro-3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanoneMonohydrochloride (Intermediate 5 Monohydrochloride Salt)

[1298] Intermediate 2 (34.17 g) and Intermediate 3 (54.48 g) werereacted according to the process for synthesizing Intermediate 4 inReference Example 4. The reaction product was-purified by silica gelcolumn chromatography (eluted with ethyl acetate/n-hexane (1/4 to 3/7)),solidified as a hydrochloride salt, triturated with 2-propanol, and thendried under reduced pressure to give the title compound (Intermediate 5;17.64 g).

[1299]¹H-NMR (300 MHz, DMSO-d₆; hydrochloride salt) δ 3.27 (s, 3H), 3.72(m, 2H), 4.49-4.72 (m, 4H), 4.93 (m, 2H), 5.16 (br, 2H), 6.55 (d, 1H,J=8.0), 6.97 (d, 1H, J=1.9), 7.11 (t, 1H, J=7.7), 7.18-7.35 (m, 6H),7.39-7.58 (m, 4H), 7.65-7.78 (m, 3H), 7.83 (d, 1H, J=8.5), 7.89 (d, 1H,J=8.5), 7.98 (d, 1H, J=7.7), 8.08 (s, 1H), 11.01 (br, 1H), 11.27 (s,1H);

[1300] R_(f)=0.51 (1/1 ethyl acetate/n-hexane).

Reference Example 6

[1301]1-[3-[(benzyl)(methylsulfonyl)amino]phenyl]-2-[[2-(9H-carbazol-2-yloxy)ethyl]benzylamino]ethanoneMonohydrochloride (Intermediate 6 Monohydrochloride Salt)

[1302] Intermediate 1 (151.34 g) and Intermediate 3 (263.05 g) werereacted according to the process for synthesizing Intermediate 4 inReference Example 4. The reaction product was solidified as ahydrochloride salt (222.58 g), triturated with 2-propanol (2L+1L), andthen dried at 40° C. under reduced pressure to give a crude solid(187.94 g). This was further triturated with methanol (710 mL),collected by filtration, dried at 40° C. under reduced pressure,triturated again with methanol (600 mL), collected by filtration, andthen dried at 40° C. under reduced pressure for 12 hours to give thetitle compound (Intermediate 6; 159.29 g).

[1303]¹H-NMR (300 MHz, DMSO-d₆; hydrochloride salt) δ 3.12 (s, 3H), 3.72(br, 2H), 4.46-4.68 (m, 4H), 4.95 (s, 2H), 5.12 (br, 2H), 6.52 (d, 1H,J=7.7), 6.95 (d, 1H, J=1.9), 7.11 (t, 1H, J=7.7), 7.16-7.34 (m, 6H),7.40-7.50 (m, 4H), 7.54 (t, 1H, J=8.2), 7.66-7.78 (m, 3H), 7.83 (d, 1H,J=7.7), 7.85 (d, 1H, J=8.5), 7.95-8.02 (m, 2H), 10.79 (br, 1H), 11.23(br, 1H);

[1304] R_(f)=0.43 (1/1 ethyl acetate/n-hexane).

Reference Example 7

[1305] 2-dimethylaminoacetophenone Monohydrobromide (Intermediate 7Mono-HBr Salt)

[1306] Phenacyl bromide (25 g, 126 mmol; mfd. by TOKYO KASEI) anddiethyl ether (251 mL) were placed in a 500 mL recovery flask equippedwith a teflon-coated stirrer. The flask was placed on an ice bath. Anaqueous 50% dimethylamine solution (113 g, 1.26 mol; mfd. by NacalaiTesque) was added dropwise with vigorous stirring, followed by stirringat 0° C. for 8 hours. The reaction mixture was concentrated underreduced pressure. Water contained in the thus obtained residue wasremoved by azeotrope with toluene. The orange powder obtained byrecrystallization from ethanol was then washed with n-hexane to give thetitle compound (Intermediate 7 mono-HBr salt; 19.2 g, 78.6 mmol, yield63%) as a white solid.

[1307]¹H-NMR (400 MHz, DMSO-d₆) δ 2.93 (s, 6H), 5.15 (s, 2H), 7.63 (t,2H, J=7.6), 7.77 (t, 1H, J=7.6), 8.00 (d, 2H, J=7.2), 9.88 (s, 1H).

Reference Example 8

[1308] Synthesis of (methyl)(phenyl)aminoacetone (Intermediate 8)

[1309] DMF (31 mL), bromoacetone (4.25 g, 31 mmol; mfd. by TOKYO KASEI),N-methylaniline (4.93 g, 46 mmol; mfd. by TOKYO KASEI) and propyleneoxide (22 mL, 314 mmol; mfd. by TOKYO KASEI) were added to a 100 mLrecovery flask equipped with a teflon-coated stirrer and a refluxcolumn. The resulting mixture was stirred at 50° C. for 15 hours. Afterallowed to cool by itself, the mixture was extracted with ethyl acetateand water. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, filtered, and then concentrated under reducedpressure. The residue was subjected to a silica gel chromatographytreatment (silica gel, 450 g; n-hexane/ethyl acetate (5/1)) to give thetitle compound (Intermediate 8; 2.43 g, 14.9 mmol, yield 48%) as thesecond fraction.

[1310]¹H-NMR (400 MHz, CDCl₃) δ 2.13 (s, 3H), 3.06 (s, 3H), 4.01 (s,2H), 6.62 (dd, 2H, J=8.8, 0.8), 6.72-6.77 (m, 1H), 7.19-7.28 (m, 2H).

Reference Example 9

[1311] Synthesis of Benzyloxyacetone (Intermediate 9)

[1312] THF (30 mL) and sodium hydride (60% oil suspension; 4.8 g, 120mmol; mfd. by Nacalai Tesque) were placed in a 100 mL Schlenk typereaction tube equipped with a teflon-coated stirrer. The tube was placedon an ice bath. Benzyl alcohol (13.0 g, 120 mmol; mfd. by NacalaiTesque) diluted with THF (10 mL) was added dropwise with a syringe. Theice bath was removed and the reaction mixture was allowed to warm toroom temperature, followed by stirring for 1 hour. The tube was placedon an ice bath and ethyl 4-chloro-acetoacetate (9.88 g, 60 mmol) dilutedwith THF (10 mL) was added dropwise with a syringe. After removing theice bath, the reaction mixture was stirred at 25° C. for 12 hours, andthen extracted with ethyl acetate and 5% hydrochloric acid. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, filtered, and then concentrated under reduced pressure. Theresidue was subjected to a silica gel chromatography treatment (silicagel, 1.0 kg; hexane/ethyl acetate (5/1)) to give ethyl4-benzyloxyacetoacetate (13.2 g, 56.0 mmol, yield 93%) as the firstfraction.

[1313]¹H-NMR (400 MHz, CDCl₃) δ 1.24 (t, 3H, J=6.8), 3.54 (s, 2H),4.11-4.20 (m, 4H), 4.59 (s, 2H), 7.31-7.37 (m, 5H).

[1314] The above obtained ethyl 4-benzyloxyacetoacetate (3.0 g, 12.7mmol), distilled water (25 mL), ethanol (20 mL) and p-toluene-sulfonicacid (483 mg, 2.54 mmol; mfd. by KANTOU KAGAKU) were placed in a 100 mLrecovery flask equipped with a teflon-coated stirrer. The flask wasplaced on an oil bath and the resulting mixture was refluxed for 24hours. The oil bath was removed and the mixture was extracted with ethylacetate and an aqueous saturated sodium hydrogencarbonate solution. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, filtered, and then concentrated under reduced pressure.The residue was subjected to an abbreviated distillation treatment togive benzyloxyacetone (Intermediate 9; 1.59 g, 9.68 mmol, yield 76%).

[1315]¹H-NMR (400 MHz, CDCl₃) δ 2.17 (s, 3H), 4.06 (s, 2H), 4.60 (s,2H), 7.31-7.37 (m, 5H);

[1316]¹³C-NMR (100 MHz, CDCl₃) δ 26.42, 73.31, 75.26, 76.68, 127.88,128.02, 128.52, 137.13, 206.70.

Reference Example 10

[1317] Synthesis of 2-(tert-butyldiphenylsilyl)oxyacetophenone(Intermediate 10)

[1318] 2-Hydroxyacetophenone (4.67 g, 34.3 mmol; mfd. by TOKYO KASEI),imidazole (3.50 g, 51.5 mmol; mfd. by Nacalai Tesque) anddichloromethane (20 mL) were placed in a 50 mL recovery flask equippedwith a teflon-coated stirrer. The flask was placed on an ice bath.Tert-butyldiphenylchlorosilane (11.3 g, 41.2 mmol; mfd. by TOKYO KASEI)was added dropwise under an argon stream. The ice bath was removed andthe reaction mixture was stirred at 25° C. for 12 hours. The organiclayer was washed with 5% hydrochloric acid and saturated brine, driedover anhydrous sodium sulfate, filtered, and then concentrated underreduced pressure. The thus obtained yellow solid was subjected to asilica gel chromatography treatment (silica gel, 700 g; hexane/diethylether (19/1)) to give the title compound (Intermediate 10; 9.73 g, 26.0mmol, yield 76%) as the second fraction.

[1319]¹H-NMR (270 MHz, CDCl₃) δ 1.07 (s, 9H), 4.91 (s, 2H), 7.35-7.53(m, 9H), 7.69-7.84 (m, 6H).

[1320] All the publications, patents and patent applications cited inthis specification are incorporated herein in their entities byreference.

INDUSTRIAL UTILITY

[1321] The present invention provides a novel and practically usefulprocess for the preparation of optically active secondary alcoholshaving a nitrogenous or oxygenic functional group which comprisesasymmetrically hydrogenating a ketone compound having a nitrogenous oroxygenic functional group at any of the α-, β- and γ-positions with aruthenium/optically active bidentate phosphine/diamine complex as acatalyst either in the presence of hydrogen or in the presence ofhydrogen and a base with good selectivity for the functional groups,good enantioselectivity and high efficiency.

[1322] Optically active secondary alcohols containing an amino group,optically active diols and optically active hydroxyaldehydes which arevery useful in a variety of applications, for example, as anintermediate for producing medicaments and pesticides or as medicamentsand pesticides per se, can be produced by sequentially or simultaneouslyremoving the nitrogen- and/or oxygen-protecting groups of the opticallyactive secondary alcohols obtained by the process of the presentinvention.

1. A process for the preparation of an optically active secondaryalcohol represented by the general formula (3) having a nitrogenous oroxygenic functional group at any of the α-, β- and γ-positions:

wherein n is an integer of from 0 o 2; R¹ represents: (a) astraight-chain lower alkyl group, (b) an optionally substitutedmonocyclic aromatic hydrocarbon ring group, (c) an optionallysubstituted fused bicyclic aromatic hydrocarbon ring group, (d) anoptionally substituted fused tricyclic aromatic hydrocarbon ring group,(e) an optionally substituted monocyclic heteroaromatic ring group, (f)an optionally substituted fused bicyclic heteroaromatic ring group, or(g) an optionally substituted fused tricyclic heteroaromatic ring group;A represents: (a) CH₂NR²R³, (b) CH₂OR⁴, or (c) CH(OR¹⁵)₂; R² represents:(a) an acyl or alkyloxycarbonyl group, (b) an optionally substitutedstraight-chain alkyl group, (c) an optionally substituted branched-chainalkyl group, (d) an optionally substituted cyclic alkyl group, (e) anoptionally substituted alkenyl group, (f) an optionally substitutedaralkyl group, (g) an optionally substituted aryl group, (h) aheteroatom-containing saturated carbon chain group, (i) aheteroatom-containing unsaturated carbon chain group, (j) an optionallysubstituted heteromonocyclic group, (k) an optionally substitutedheteropolycyclic group, or (l) a composite group consisting of memberssuitably selected from any of (b) to (k); when R² is (a) an acyl oralkyloxycarbonyl group among the above groups, R³ represents: (a)hydrogen, (b) an optionally substituted straight-chain alkyl group, (c)an optionally substituted branched-chain alkyl group, (d) an optionallysubstituted cyclic alkyl group, (e) an optionally substituted alkenylgroup, (f) an optionally substituted aralkyl group, (g) an optionallysubstituted aryl group, (h) a heteroatom-containing saturated carbonchain group, (i) a heteroatom-containing unsaturated carbon chain group,(j) an optionally substituted heteromonocyclic group, (k) an optionallysubstituted heteropolycyclic group, or (l) a composite group consistingof members suitably selected from any of (b) to (k); alternatively, whenR² is any group other than (a) an acyl or alkyloxycarbonyl group amongthe above groups, R³ represents: (a) an optionally substitutedstraight-chain alkyl group, (b) an optionally substituted branched-chainalkyl group, (c) an optionally substituted cyclic alkyl group, (d) anoptionally substituted alkenyl group, (e) an optionally substitutedaralkyl group, (f) an optionally substituted aryl group, (g) aheteroatom-containing saturated carbon chain group, (h) aheteroatom-containing unsaturated carbon chain group, (i) an optionallysubstituted heteromonocyclic group, (j) an optionally substitutedheteropolycyclic group, or (k) a composite group consisting of memberssuitably selected from any of (a) to (j); and R² and R³ may be linked toeach other to form a heterocyclic group; R⁴ represents: (a) anoptionally substituted straight-chain alkyl group, (b) an optionallysubstituted branched-chain alkyl group, (c) an optionally substitutedcyclic alkyl group, (d) an optionally substituted benzyl group, (e) anoptionally substituted aralkyl group, (f) an optionally substituted arylgroup, (g) a heteroatom-containing saturated carbon chain group, (h) aheteroatom-containing unsaturated carbon chain group, (i) an optionallysubstituted heteromonocyclic group (j) an optionally substitutedheteropolycyclic group, (k) a composite group consisting of memberssuitably selected from any of (a) to (j), or (l) an organosilicon grouprepresented by SiR⁵R⁶R⁷; R⁵, R⁶ and R⁷ each independently represent: (a)a straight-chain or branched-chain lower alkyl group, or (b) a phenylgroup; R¹⁵ represents: (a) a straight-chain lower alkyl group, (b) abranched-chain lower alkyl group, (c) a cyclic lower alkyl group, (d) anoptionally substituted phenyl group, (e) an optionally substitutedbenzyl group, or (f) alternatively, two R¹⁵ are bonded to each other toform a cyclic ketal group; and * represents an asymmetric carbon atom,which comprises asymmetrically hydrogenating a ketone compoundrepresented by the general formula (1) having a nitrogenous or oxygenicfunctional group at any of the α-, β- and γ-positions:

wherein R¹, A and n are as defined above, or a mineral or organic acidsalt thereof, with a catalyst in the presence of hydrogen or in thepresence of hydrogen and a base, the catalyst being aruthenium/optically active bidentate phosphine/diamine complexrepresented by the general formula (2):

wherein m is an integer of from 0 to 2; X and Y may be covalently orionically bonded to the ruthenium metal, and they independentlyrepresent: (a) hydrogen, (b) halogen, (c) an alkoxy group, (d) acarboxyl group, or (e) other anion radical; Ar¹ and Ar² independentlyrepresent a phenyl group substituted with from zero to five substituentsselected from straight-chain or branched-chain lower alkyl group,halogen or lower alkoxy group; R⁸ represents: (a) hydrogen, (b) a loweralkyl group, (c) a lower alkoxy group, or (d) N(R¹⁴)₂ wherein R¹⁴represents a lower alkyl group; R⁹ represents: (a) hydrogen, (b) a loweralkyl group, or (c) a lower alkoxy group; R¹⁰ represents: (a) a loweralkyl group, or (b) a lower alkoxy group; the dashed line linking one R¹to the other R¹⁰ means that one R¹⁰ may be bonded to the other R¹⁰ viaan oxygen atom; one dashed line linking R⁹ to R¹⁰, and the other dashedline linking R⁹ to R¹⁰ independently mean that each pair of R⁹ and R¹⁰taken together with the benzene ring to which they are attached may forma ring selected from the following rings: (a) an optionally substitutedtetralin ring, (b) an optionally substituted naphthalene ring, and (c)an optionally substituted 1,3-benzodioxole ring; R¹¹ represents: (a)hydrogen, (b) a straight-chain lower alkyl group, (c) a branched-chainlower alkyl group, (d) a cyclic lower alkyl group, (e) a phenyl groupsubstituted with from zero to five substituents selected from loweralkyl groups or lower alkoxy groups, (f) a 1-naphthyl group substitutedwith from zero to seven substituents selected from lower alkyl groups orlower alkoxy groups, or (g) a 2-naphthyl group substituted with fromzero to seven substituents selected from lower alkyl groups or loweralkoxy groups; provided that (I) when R¹¹ is hydrogen, then R¹² and R¹³are independently represent: (a) hydrogen, (b) a straight-chain loweralkyl group, (c) a branched-chain lower alkyl group, (d) a cyclic loweralkyl group, (e) a phenyl group substituted with from zero to fivesubstituents selected from lower alkyl groups or lower alkoxy groups,(f) a 1-naphthyl group substituted with from zero to seven substituentsselected from lower alkyl groups or lower alkoxy groups, (g) a2-naphthyl group substituted with from zero to seven substituentsselected from lower alkyl groups or lower alkoxy groups, or (h)alternatively, R¹² and R¹³ may be bonded to each other to form a ringselected from: (h-1) a cycloalkyl ring, or (h-2) a heteroatom-containingheterocyclic ring; or (II) when R¹¹ is other than hydrogen, then R¹²represents: (a) a straight-chain lower alkyl group, (b) a branched-chainlower alkyl group, (c) a cyclic lower alkyl group, (d) a phenyl groupsubstituted with from zero to five substituents selected from loweralkyl groups or lower alkoxy groups, (e) a 1-naphthyl group substitutedwith from zero to seven substituents selected from lower alkyl groups orlower alkoxy groups, or (f) a 2-naphthyl group substituted with fromzero to seven substituents selected from lower alkyl groups or loweralkoxy groups; and R¹³ represents: (a) hydrogen, (b) a lower alkylgroup, or (c) a benzyl group.
 2. A process for the preparation of anoptically active secondary alcohol as claimed in claim 1,wherein R¹ andA in the general formula (1) each comprise no acidic substituents.
 3. Aprocess for the preparation of an optically active secondary alcohol asclaimed in claim 1 or 2, wherein Ar¹ and Ar² in the general formula (2)each independently represent a phenyl group having from two to fivesubstituents selected from the group consisting of straight-chain orbranched-chain lower alkyl groups, halogens, and lower alkoxy groupsprovided that at least two of the said substituents are straight-chainor branched-chain lower alkyl groups.
 4. A process for the preparationof an optically active secondary alcohol as claimed in any of claims 1to 3, wherein in the general formula (1), n is 0; A is CH₂NR²R³; R¹ is aphenyl group having at 3-position a nitro group, an amino group, orN(CH₂C₆H₅)SO₂R¹⁶ wherein R¹⁶ is a methyl group or a benzyl group, and at4-position hydrogen, halogen, or a benzyloxy group; R² is an acyl group,an alkyloxycarbonyl group, or a benzyl group; and R³ is an ethyl groupwhich is bonded at its end to the fused tricyclic ring group via anoxygen atom.